{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","name":"Research Synthesis: Exosomes Extracellular Vesicles — full paper","doi":"10.17605/OSF.IO/VTG79","doi_status":"minted","osf_url":"https://osf.io/vtg79/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dbe570ea655e47b1/chain","content_hash":"sha256:8b3d52903329e950fc6e175396fc13a235a74e6cfd072bd35382832a98268c54","provenance_passport":{"publication_id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","submission_id":"64376976-7a7c-4298-8d1a-61b9a07529f4","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:8b3d52903329e950fc6e175396fc13a235a74e6cfd072bd35382832a98268c54","persistent_identifiers":{"doi":"10.17605/OSF.IO/VTG79","osf_url":"https://osf.io/vtg79/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":null,"provenance":{"dw_artifact_id":"claim_dbe570ea655e47b1","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dbe570ea655e47b1/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","object_type":"publication","parent_object_id":"64376976-7a7c-4298-8d1a-61b9a07529f4","title":"Research Synthesis: Exosomes Extracellular Vesicles — full paper","body_markdown":"# Research Synthesis: Exosomes Extracellular Vesicles — full paper\n\n## Abstract\n\nThis paper synthesizes exosomes extracellular vesicles as an aging-related intervention across 56 included source papers and 2834 high-confidence extracted claims.\n\nThe evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-exosomes_extracellular_vesicles-v06-DAILY-2026-05-31T23-15-05Z`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-05-31.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `exosomes AND aging AND human`\n- `extracellular vesicles AND skin aging`\n- `MSC exosomes AND clinical trial`\n- `exosome therapy AND safety`\n- `extracellular vesicles AND immune aging`\n\n### Eligibility criteria\n- Sources whose primary content addresses exosomes extracellular vesicles.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 191 records in the receipt-candidate union, 71 were classified as source candidates and 56 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 191 |\n| Classified source candidates | 71 |\n| No extractable claims | 37 |\n| None-only claim binding | 15 |\n| Partial/none-only claim binding | 52 |\n| Partial-only candidates | 8 |\n| Strict high-confidence sources | 8 |\n| Admitted final sources | 56 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Source verification in the public bundle is limited to reference-level metadata; reported statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=36; claims=1715 | null signal in 33/36 sources | 18 indirect; 2 mechanistic; 16 review | limited corpus depth in this outcome class |\n| Immune | n=7; claims=165 | unclear signal in 2/7 sources | 2 indirect; 1 mechanistic; 4 review | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=6; claims=413 | null signal in 6/6 sources | 4 indirect; 2 review | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=4; claims=142 | null signal in 4/4 sources | 4 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=1; claims=251 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Deficiency Prevalence | n=1; claims=9 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Longevity | n=1; claims=139 | mixed signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n36 included sources were assigned to this outcome class. Directional coding: null=33, positive=2, unclear=1. Directness coding: indirect=18, mechanistic=2, review=16.\n\n### Immune Outcomes\n\n7 included sources were assigned to this outcome class. Directional coding: mixed=2, negative=1, null=2, unclear=2. Directness coding: indirect=2, mechanistic=1, review=4.\n\n### Safety Comorbidity Outcomes\n\n6 included sources were assigned to this outcome class. Directional coding: null=6. Directness coding: indirect=4, review=2.\n\n### Skeletal Fracture Bone Outcomes\n\n4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: review=4.\n\n### Cardiometabolic Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Deficiency Prevalence Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Longevity Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: review=1.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nA fundamental limitation of this synthesis is the composition of the curated evidence corpus. Although 56 papers were included, the majority are systematic reviews and meta-analyses of preclinical animal studies rather than primary human randomized controlled trials. For example, evidence for osteoporosis-related bone outcomes (Zhang 2025, He 2023, Zhang 2025b), periodontal regeneration (Zhou 2025), diabetic peripheral neuropathy (Lu 2025), and renal ischemia-reperfusion injury (Wang 2025) derives entirely from preclinical models.\n\nSeveral clinically important outcomes are represented by only a single study, precluding any within-corpus replication or assessment of consistency. The safety and efficacy of exosomes for knee osteoarthritis, assessed in Bolandnazar 2024 as a randomized, triple-blind, placebo-controlled trial, showed no statistically significant difference between EV-treated and placebo groups for clinical outcomes — yet this single null finding cannot be contextualized against other human trials because no other OA-specific RCT was included. Single-trial findings, whether positive or null, carry substantial uncertainty regarding reproducibility.\n\nThe enrolled populations across the included studies are narrow and raise external validity concerns. Only one observational study (Doi 2025) explicitly examined frail or sarcopenic adults with obstructive pulmonary disease, and that study focused on EV small-RNA profiles as biomarkers rather than therapeutic intervention. Consequently, the synthesis cannot directly address whether exosome-based therapies benefit older adults with age-related functional decline, and extrapolation from younger or comorbidity-specific cohorts remains speculative.\n\nThe corpus lacks long-term mortality and hard clinical endpoint data. No included study was designed with long-term survival as a primary endpoint in the aging-relevant population. The mechanism-to-clinic gap therefore remains wide: while preclinical data convincingly demonstrate anti-inflammatory and regenerative properties of EVs (Zhu 2025, Hong 2025), the translation to clinically meaningful, sustained benefit in older adults is not established by the available human evidence.\n\n## Conclusion\n\nFor exosomes extracellular vesicles, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support exosomes extracellular vesicles as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 56 included sources on Extracellular vesicles across 7 outcome classes and 668 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 56 curated reference papers, the evidence base for Extracellular vesicles shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: immune. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Extracellular vesicles anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nAdditional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the disagreement between Pineiro-Ramil 2025 and Hong 2025 on immune (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nAdditional corpus sources included animal/preclinical evidence; prior reviews in the corpus (Wu 2025, Wang 2025, Hong 2025, Wang 2025b, Su 2024) emphasize convergent signals on Extracellular vesicles. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Outcome class | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| immune | 0 | 7 | mixed, negative, null, unclear | conflict-resolution gap |\n| longevity | 0 | 1 | mixed | direct clinical gap |\n| cardiometabolic | 0 | 1 | null | direct clinical gap |\n| contextual adjacent evidence | 0 | 36 | null, positive, unclear | direct clinical gap |\n| deficiency prevalence | 0 | 1 | null | direct clinical gap |\n| safety and comorbidity | 0 | 6 | null | direct clinical gap |\n| skeletal, fracture, and bone | 0 | 4 | null | direct clinical gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | immune: conflict-resolution gap | 0 direct and 7 indirect sources; direction profile: mixed, negative, null, unclear |\n| P2 | longevity: direct clinical gap | 0 direct and 1 indirect source; direction profile: mixed |\n| P3 | cardiometabolic: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | contextual adjacent evidence: direct clinical gap | 0 direct and 36 indirect sources; direction profile: null, positive, unclear |\n| P5 | deficiency prevalence: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Extracellular vesicles should target the **immune** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\nAdditional corpus sources included animal/preclinical evidence; - Wu 2025; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=longevity; direction=mixed; representative statistic=P = 0.0003.\n- Wang 2025; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=contextual other; direction=positive; representative statistic=P < 0.001.\n- Hong 2025; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=immune; direction=mixed; representative statistic=P < 0.00001.\n- Wang 2025b; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=contextual other; direction=positive; representative statistic=P < 0.00001.\n- Su 2024; Review / meta-analysis; tier=B1; directness=review; N=—; population=adults; endpoint=immune; direction=unclear.\n- Jafarzadeh 2025; Review / meta-analysis; tier=B2; directness=review; N=—; population=—; endpoint=contextual other; direction=null; representative statistic=P < 0.05.\n- Leung 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=cardiometabolic; direction=null; representative statistic=P = 0.0098.\n- Bolandnazar 2024; RCT; tier=B2; directness=indirect; N=—; population=adults; endpoint=safety comorbidity; direction=null.\n- Kishta 2025; RCT; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P = 0.001.\n- Behrangi 2026; Review / meta-analysis; tier=B2; directness=review; N=—; population=—; endpoint=safety comorbidity; direction=null; representative statistic=P < 0.001.\n\n### Load-Bearing Tensions\n\nAdditional corpus sources included animal/preclinical evidence; - Severity 4 disagreement: Pineiro-Ramil 2025 vs Hong 2025; Pineiro-Ramil 2025 (unclear) vs Hong 2025 (mixed) on immune\n- Severity 4 disagreement: Pineiro-Ramil 2025 vs Shi 2021; Pineiro-Ramil 2025 (unclear) vs Shi 2021 (mixed) on immune\n- Severity 4 disagreement: Hong 2025 vs Zeng 2025; Hong 2025 (mixed) vs Zeng 2025 (null) on immune\n- Severity 4 disagreement: Hong 2025 vs Pan 2025; Hong 2025 (mixed) vs Pan 2025 (negative) on immune\n- Severity 4 disagreement: Hong 2025 vs Dai 2026; Hong 2025 (mixed) vs Dai 2026 (null) on immune\n- Severity 4 disagreement: Hong 2025 vs Su 2024; Hong 2025 (mixed) vs Su 2024 (unclear) on immune\n- Severity 4 disagreement: Zeng 2025 vs Shi 2021; Zeng 2025 (null) vs Shi 2021 (mixed) on immune\n- Severity 4 disagreement: Pan 2025 vs Shi 2021; Pan 2025 (negative) vs Shi 2021 (mixed) on immune\n\nAdditional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Delen 2024, Ahmed 2024, Dhaliwal 2026, Luo 2024, Wei 2026, Zhang 2024, Andrews 2025, Bozbas 2024, Zamanian 2024, Kalluri 2025, Johnson 2023, Chernoff 2026, Jeppesen 2025, Ye 2024, Akhlaghpasand 2024, Santos 2026, Fang 2025, Kabatas 2025, Grueso-Navarro 2025, Habibi 2025, Wang 2025c, Hyun 2025, Estupinan 2025, Niu 2026, Civelek 2024, Zhu 2022, Li 2025, Svolacchia 2024, Ghanem 2025, Zhong 2023, Mitra 2026, Vreones 2022, Antoniewicz 2024, Su 2025.\n\n## References\n\n- **Jafarzadeh 2025.** _Effectiveness of regenerative medicine for skin lightening and rejuvenation: a systematic review of extracellular vesicles and conditioned media._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04592-z. PMID: 41013717.\n- **Leung 2025.** _Glycolytic control proteins in urinary extracellular vesicles are elevated during kidney transplant T cell-mediated rejection._ BMC Nephrology, 2025. DOI: 10.1186/s12882-025-04196-y. PMID: 40481420.\n- **Bolandnazar 2024.** _Safety and efficacy of placental mesenchymal stromal cells-derived extracellular vesicles in knee osteoarthritis: a randomized, triple-blind, placebo-controlled clinical trial._ BMC Musculoskeletal Disorders, 2024. DOI: 10.1186/s12891-024-07979-w. PMID: 39465400.\n- **Wu 2025.** _Efficacy and safety of mesenchymal stem/stromal cells and their derived extracellular vesicles for acute respiratory distress syndrome: a systematic review and meta-analysis._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04644-4. PMID: 41023747.\n- **Kishta 2025.** _The transforming role of wharton’s jelly mesenchymal stem cell-derived exosomes for diabetic foot ulcer healing: a randomized controlled clinical trial._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04690-y. PMID: 41084065.\n- **Behrangi 2026.** _A systematic review of clinical evidence on the efficacy and safety of conditioned media, platelet-rich fibrin, stromal vascular fraction, extracellular vesicles, and stem cells in androgenetic alopecia._ Stem Cell Research & Therapy, 2026. DOI: 10.1186/s13287-026-05016-2. PMID: 41987228.\n- **Zhu 2025.** _Mesenchymal stem cells-derived small extracellular vesicles and apoptotic extracellular vesicles for wound healing and skin regeneration: a systematic review and meta-analysis of preclinical studies._ Journal of Translational Medicine, 2025. DOI: 10.1186/s12967-024-05744-0. PMID: 40128791.\n- **Lu 2025.** _Cell-derived exosome therapy for diabetic peripheral neuropathy: a preclinical animal studies systematic review and meta-analysis._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04432-0. PMID: 40490808.\n- **Delen 2024.** _A systematic review and meta‐analysis of clinical trials assessing safety and efficacy of human extracellular vesicle‐based therapy._ Journal of Extracellular Vesicles, 2024. DOI: 10.1002/jev2.12458. PMID: 38958077.\n- **Wang 2025.** _Protective role of exosomes in renal ischemia-reperfusion injury: a systematic review and meta-analysis._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1653907. PMID: 40978485.\n- **Zhou 2025.** _Therapeutic effect of mesenchymal stem cell-derived exosome therapy for periodontal regeneration: a systematic review and meta-analysis of preclinical trials._ Journal of Orthopaedic Surgery and Research, 2025. DOI: 10.1186/s13018-024-05403-6. PMID: 39780243.\n- **He 2023.** _Osteoporosis treatment using stem cell-derived exosomes: a systematic review and meta-analysis of preclinical studies._ Stem Cell Research & Therapy, 2023. DOI: 10.1186/s13287-023-03317-4. PMID: 37038180.\n- **Ahmed 2024.** _Stem Cell Extracellular Vesicles as Anti-SARS-CoV-2 Immunomodulatory Therapeutics: A Systematic Review of Clinical and Preclinical Studies._ Stem Cell Reviews and Reports, 2024. DOI: 10.1007/s12015-023-10675-2. PMID: 38393666.\n- **Dhaliwal 2026.** _The Use of Microneedling With Exosomes in Dermatology: A Systematic Review._ Journal of Cosmetic Dermatology, 2026. DOI: 10.1111/jocd.70881. PMID: 42027180.\n- **Hong 2025.** _Stem Cell-Derived Extracellular Vesicles for Acute Pancreatitis: a Systematic Review and Meta-analysis of Preclinical Studies._ Stem Cell Reviews and Reports, 2025. DOI: 10.1007/s12015-025-10852-5. PMID: 39964640.\n- **Luo 2024.** _Stem cell-derived extracellular vesicles in premature ovarian failure: an up-to-date meta-analysis of animal studies._ Journal of Ovarian Research, 2024. DOI: 10.1186/s13048-024-01489-y. PMID: 39252114.\n- **Shi 2021.** _Preclinical efficacy and clinical safety of clinical‐grade nebulized allogenic adipose mesenchymal stromal cells‐derived extracellular vesicles._ Journal of Extracellular Vesicles, 2021. DOI: 10.1002/jev2.12134. PMID: 34429860.\n- **Wang 2025b.** _Mesenchymal stem cell-derived exosomes for the treatment of knee osteoarthritis: a systematic review and meta-analysis based on rat model._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1588841. PMID: 40529485.\n- **Pineiro-Ramil 2025.** _Mesenchymal stromal cells-derived extracellular vesicles in cartilage regeneration: potential and limitations._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04135-6. PMID: 39849578.\n- **Wei 2026.** _Therapeutic effects of stem cell–derived extracellular vesicles in animal models of intervertebral disc degeneration: a systematic review and meta-analysis of species differences and delivery strategies._ Frontiers in Bioengineering and Biotechnology, 2026. DOI: 10.3389/fbioe.2026.1749916. PMID: 41693926.\n- **Zhang 2024.** _The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis._ BMC Pulmonary Medicine, 2024. DOI: 10.1186/s12890-024-02910-4. PMID: 38481171.\n- **Andrews 2025.** _PSMA + Extracellular Vesicles Are a Biomarker for SABR in Oligorecurrent Prostate Cancer: Analysis from the STOMP-like and ORIOLE Trial Cohorts._ Clinical Cancer Research, 2025. DOI: 10.1158/1078-0432.CCR-24-3027. PMID: 39820657.\n- **Bozbas 2024.** _Dietary n-3 polyunsaturated fatty acids alter the number, fatty acid profile and coagulatory activity of circulating and platelet-derived extracellular vesicles: a randomized, controlled crossover trial._ The American Journal of Clinical Nutrition, 2024. DOI: 10.1016/j.ajcnut.2024.03.008. PMID: 38484976.\n- **Zhang 2025.** _Therapeutic effects of mesenchymal stem cell-derived extracellular vesicles in osteoporosis models: a systematic review and meta-analysis of preclinical studies._ Frontiers in Endocrinology, 2025. DOI: 10.3389/fendo.2025.1625969. PMID: 41036147.\n- **Zamanian 2024.** _Human placental mesenchymal stromal cell‐derived small extracellular vesicles as a treatment for severe COVID‐19: A double‐blind randomized controlled clinical trial._ Journal of Extracellular Vesicles, 2024. DOI: 10.1002/jev2.12492. PMID: 39051747.\n- **Kalluri 2025.** _Engineered exosomes with Kras G12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates._ Nature Communications, 2025. DOI: 10.1038/s41467-025-63718-2. PMID: 41027940.\n- **Johnson 2023.** _First‐in‐human clinical trial of allogeneic, platelet‐derived extracellular vesicles as a potential therapeutic for delayed wound healing._ Journal of Extracellular Vesicles, 2023. DOI: 10.1002/jev2.12332. PMID: 37353884.\n- **Chernoff 2026.** _Human Placental Mesenchymal Stem Cell-Derived Exosomes in Wound Healing and Scar Therapy: A Systematic Review and Meta-analysis._ Aesthetic Surgery Journal, 2026. DOI: 10.1093/asj/sjaf163. PMID: 41800724.\n- **Jeppesen 2025.** _Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties._ Nature Cell Biology, 2025. DOI: 10.1038/s41556-025-01621-0. PMID: 39984653.\n- **Zhang 2025b.** _The effect of bone marrow mesenchymal stem cell-derived extracellular vesicles on bone mineral density and microstructure in osteoporosis: A systematic review and meta-analysis of preclinical studies._ PLOS One, 2025. DOI: 10.1371/journal.pone.0327011. PMID: 40587472.\n- **Ye 2024.** _Repair of spinal cord injury by bone marrow mesenchymal stem cell-derived exosomes: a systematic review and meta-analysis based on rat models._ Frontiers in Molecular Neuroscience, 2024. DOI: 10.3389/fnmol.2024.1448777. PMID: 39169950.\n- **Akhlaghpasand 2024.** _Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial._ Stem Cell Research & Therapy, 2024. DOI: 10.1186/s13287-024-03868-0. PMID: 39183334.\n- **Santos 2026.** _The Effect of Cigarettes and E-Cigarettes on Epithelial-Derived Extracellular Vesicles: A Systematic Review._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27062787. PMID: 41898645.\n- **Fang 2025.** _Extracellular vesicles from bronchoalveolar lavage fluid provide insights into the inhaled corticosteroids treatment response in COPD._ Respiratory Research, 2025. DOI: 10.1186/s12931-025-03330-6. PMID: 40739568.\n- **Kabatas 2025.** _Efficacy and safety of exosomes from Wharton’s Jelly-derived mesenchymal stem cells in traumatic brain injury._ World Journal of Critical Care Medicine, 2025. DOI: 10.5492/wjccm.v14.i4.103782. PMID: 41377533.\n- **Grueso-Navarro 2025.** _MicroRNAs in Plasma-Derived Extracellular Vesicles as Non-Invasive Biomarkers for Eosinophilic Esophagitis._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26020639. PMID: 39859353.\n- **Habibi 2025.** _Efficacy of topical mesenchymal stem cell exosome in Sjögren’s syndrome-related dry eye: a randomized clinical trial._ BMC Ophthalmology, 2025. DOI: 10.1186/s12886-025-04078-9. PMID: 40394561.\n- **Wang 2025c.** _Injection of human umbilical cord mesenchymal stem cells exosomes for the treatment of knee osteoarthritis: from preclinical to clinical research._ Journal of Translational Medicine, 2025. DOI: 10.1186/s12967-025-06623-y. PMID: 40500748.\n- **Hyun 2025.** _Safety and Anti‐Inflammatory Effects of Engineered Extracellular Vesicles (ILB‐202) for NF‐κB Inhibition: A Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Trial._ Journal of Extracellular Vesicles, 2025. DOI: 10.1002/jev2.70141. PMID: 41002119.\n- **Estupinan 2025.** _Adipose Mesenchymal Stem Cell‐Derived Exosomes Versus Platelet‐Rich Plasma Treatment for Photoaged Facial Skin: An Investigator‐Blinded, Split‐Face, Non‐Inferiority Trial._ Journal of Cosmetic Dermatology, 2025. DOI: 10.1111/jocd.70208. PMID: 40414798.\n- **Pan 2025.** _Mesenchymal stem cell–derived small extracellular vesicles (sEVs) as a therapy for sepsis-related liver injury: evidence from a systematic review and meta-analysis._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1707784. PMID: 41394125.\n- **Doi 2025.** _Small RNA Profiles of Serum-Derived Extracellular Vesicles in the Comorbid Condition of Frailty and Obstructive Pulmonary Disease: An Observational, Cross-Sectional Study._ Biomolecules, 2025. DOI: 10.3390/biom15121663. PMID: 41463319.\n- **Niu 2026.** _Altered circRNAs: a novel potential mechanism for the functions of extracellular vesicles derived from platelet-rich plasma._ Frontiers in Bioinformatics, 2026. DOI: 10.3389/fbinf.2025.1690932. PMID: 41584514.\n- **Civelek 2024.** _Effects of exosomes from mesenchymal stem cells on functional recovery of a patient with total radial nerve injury: A pilot study._ World Journal of Stem Cells, 2024. DOI: 10.4252/wjsc.v16.i1.19. PMID: 38292440.\n- **Zhu 2022.** _Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study._ Stem Cell Research & Therapy, 2022. DOI: 10.1186/s13287-022-02900-5. PMID: 35619189.\n- **Li 2025.** _Clinical investigation on nebulized human umbilical cord MSC-derived extracellular vesicles for pulmonary fibrosis treatment._ Signal Transduction and Targeted Therapy, 2025. DOI: 10.1038/s41392-025-02262-3. PMID: 40461474.\n- **Su 2024.** _Natural and bio-engineered stem cell-derived extracellular vesicles for spinal cord injury repair: A meta-analysis with trial sequential analysis._ Neuroscience, 2024. DOI: 10.1016/j.neuroscience.2024.10.018. PMID: 39490519.\n- **Svolacchia 2024.** _Exosomes and Signaling Nanovesicles from the Nanofiltration of Preconditioned Adipose Tissue with Skin-B ® in Tissue Regeneration and Antiaging: A Clinical Study and Case Report._ Medicina, 2024. DOI: 10.3390/medicina60040670. PMID: 38674316.\n- **Zeng 2025.** _MiRNA-loaded MSC exosomes restore autophagy flux for acute pancreatitis therapy._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1613716. PMID: 40842993.\n- **Ghanem 2025.** _Large extracellular vesicles (microvesicles) in diabetic nephropathy: a systematic review of preclinical studies._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1622280. PMID: 41142249.\n- **Zhong 2023.** _Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury._ Stem Cell Research & Therapy, 2023. DOI: 10.1186/s13287-023-03409-1. PMID: 37553595.\n- **Mitra 2026.** _Effect of Glucoraphanin on the Abundance of Nrf2 Regulated Genes Within Circulating Small Extracellular Vesicles: A Pilot Dietary Intervention._ Molecular Nutrition & Food Research, 2026. DOI: 10.1002/mnfr.70397. PMID: 41603376.\n- **Vreones 2022.** _Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin._ Aging Cell, 2022. DOI: 10.1111/acel.13754. PMID: 36515353.\n- **Antoniewicz 2024.** _Vascular Stress Markers Following Inhalation of Heated Tobacco Products: A Study on Extracellular Vesicles._ Cardiovascular Toxicology, 2024. DOI: 10.1007/s12012-024-09934-6. PMID: 39472409.\n- **Su 2025.** _The role of synovial mesenchymal stem cell-derived exosomes in cartilage repair: a systematic review._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1617874. PMID: 40635749.\n- **Dai 2026.** _Stem cell-derived exosomes in tissue regeneration of oral and maxillofacial region: A systematic review._ Medicine, 2026. DOI: 10.1097/MD.0000000000046948. PMID: 41496030.\n","metadata":{"abstract":"This paper synthesizes exosomes extracellular vesicles as an aging-related intervention across 56 included source papers and 2834 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","article_type":"rapid_evidence_synthesis","counts":{"retrieved_count":56,"selected_count":56,"review_like_count":27,"primary_like_count":29,"year_start":2021,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":null,"identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/VTG79","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"vtg79","osf_url":"https://osf.io/vtg79/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"vtg79","url":"https://osf.io/vtg79/","doi":"10.17605/OSF.IO/VTG79"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"mimo-v2.5-pro|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"dw_artifact_id":"claim_dbe570ea655e47b1","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dbe570ea655e47b1/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_dbe570ea655e47b1/chain","dw_source_artifact_id":"source_71bf339cec954d8f","dw_input_artifact_ids":["source_dbec6bff8b1244df","source_c033809789b4470c","source_e2bcadb2aabe49b4","source_fcb30f2154634332","source_7ad299bc9c744805","source_2e6e8c82d8f04ee5"],"dw_step_id":"step_63ddb4a232944bfe","dw_step_hash":"027a5719f8c76673fde85809a07ec0cec8b71d6570de5c2f977ca7d9b3ebb172","dw_status":"registered","content_hash":"sha256:8b3d52903329e950fc6e175396fc13a235a74e6cfd072bd35382832a98268c54","sha256":"sha256:8b3d52903329e950fc6e175396fc13a235a74e6cfd072bd35382832a98268c54","osf_auth_source":"oauth_agent_token"},"created_at":"2026-06-01T03:18:59.371913+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes exosomes extracellular vesicles as an aging-related intervention across 56 included source papers and 2834 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-exosomes_extracellular_vesicles-v06-DAILY-2026-05-31T23-15-05Z`.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Source verification in the public bundle is limited to reference-level metadata; reported statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"| Contextual Adjacent Evidence | n=36; claims=1715 | null signal in 33/36 sources | 18 indirect; 2 mechanistic; 16 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"| Safety and Comorbidity | n=6; claims=413 | null signal in 6/6 sources | 4 indirect; 2 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"| Skeletal, Fracture, and Bone | n=4; claims=142 | null signal in 4/4 sources | 4 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"| Cardiometabolic | n=1; claims=251 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"| Deficiency Prevalence | n=1; claims=9 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"36 included sources were assigned to this outcome class. Directional coding: null=33, positive=2, unclear=1. Directness coding: indirect=18, mechanistic=2, review=16.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"7 included sources were assigned to this outcome class. Directional coding: mixed=2, negative=1, null=2, unclear=2. Directness coding: indirect=2, mechanistic=1, review=4.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"6 included sources were assigned to this outcome class. Directional coding: null=6. Directness coding: indirect=4, review=2.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: review=4.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"A fundamental limitation of this synthesis is the composition of the curated evidence corpus. Although 56 papers were included, the majority are systematic reviews and meta-analyses of preclinical animal studies rather than primary human randomized controlled trials. For example, evidence for osteoporosis-related bone outcomes (Zhang 2025, He 2023, Zhang 2025b), periodontal regeneration (Zhou 2025), diabetic peripheral neuropathy (Lu 2025), and renal ischemia-reperfusion injury (Wang 2025) derives entirely from preclinical models.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"Several clinically important outcomes are represented by only a single study, precluding any within-corpus replication or assessment of consistency. The safety and efficacy of exosomes for knee osteoarthritis, assessed in Bolandnazar 2024 as a randomized, triple-blind, placebo-controlled trial, showed no statistically significant difference between EV-treated and placebo groups for clinical outcomes — yet this single null finding cannot be contextualized against other human trials because no other OA-specific RCT was included. Single-trial findings, whether positive or null, carry substantial uncertainty regarding reproducibility.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"The corpus lacks long-term mortality and hard clinical endpoint data. No included study was designed with long-term survival as a primary endpoint in the aging-relevant population. The mechanism-to-clinic gap therefore remains wide: while preclinical data convincingly demonstrate anti-inflammatory and regenerative properties of EVs (Zhu 2025, Hong 2025), the translation to clinically meaningful, sustained benefit in older adults is not established by the available human evidence.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"For exosomes extracellular vesicles, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support exosomes extracellular vesicles as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"This synthesis maps 56 included sources on Extracellular vesicles across 7 outcome classes and 668 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"Across 56 curated reference papers, the evidence base for Extracellular vesicles shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: immune. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Extracellular vesicles anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the disagreement between Pineiro-Ramil 2025 and Hong 2025 on immune (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.","citation_support":[],"candidate_sources":[{"study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","content_hash":"sha256:8b3d52903329e950fc6e175396fc13a235a74e6cfd072bd35382832a98268c54","nodes":[{"id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","type":"publication","title":"Research Synthesis: Exosomes Extracellular Vesicles — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes exosomes extracellular vesicles as an aging-related intervention across 56 included source papers and 2834 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_2","type":"claim","text":"The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base."},{"id":"claim_3","type":"claim","text":"Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_4","type":"claim","text":"The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_5","type":"claim","text":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-exosomes_extracellular_vesicles-v06-DAILY-2026-05-31T23-15-05Z`."},{"id":"claim_6","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Source verification in the public bundle is limited to reference-level metadata; reported statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_7","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_8","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_9","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_10","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence."},{"id":"claim_11","type":"claim","text":"| Contextual Adjacent Evidence | n=36; claims=1715 | null signal in 33/36 sources | 18 indirect; 2 mechanistic; 16 review | limited corpus depth in this outcome class |"},{"id":"claim_12","type":"claim","text":"| Safety and Comorbidity | n=6; claims=413 | null signal in 6/6 sources | 4 indirect; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_13","type":"claim","text":"| Skeletal, Fracture, and Bone | n=4; claims=142 | null signal in 4/4 sources | 4 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"| Cardiometabolic | n=1; claims=251 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_15","type":"claim","text":"| Deficiency Prevalence | n=1; claims=9 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_16","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_17","type":"claim","text":"36 included sources were assigned to this outcome class. Directional coding: null=33, positive=2, unclear=1. Directness coding: indirect=18, mechanistic=2, review=16."},{"id":"claim_18","type":"claim","text":"7 included sources were assigned to this outcome class. Directional coding: mixed=2, negative=1, null=2, unclear=2. Directness coding: indirect=2, mechanistic=1, review=4."},{"id":"claim_19","type":"claim","text":"6 included sources were assigned to this outcome class. Directional coding: null=6. Directness coding: indirect=4, review=2."},{"id":"claim_20","type":"claim","text":"4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: review=4."},{"id":"claim_21","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_22","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_23","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_24","type":"claim","text":"A fundamental limitation of this synthesis is the composition of the curated evidence corpus. Although 56 papers were included, the majority are systematic reviews and meta-analyses of preclinical animal studies rather than primary human randomized controlled trials. For example, evidence for osteoporosis-related bone outcomes (Zhang 2025, He 2023, Zhang 2025b), periodontal regeneration (Zhou 2025), diabetic peripheral neuropathy (Lu 2025), and renal ischemia-reperfusion injury (Wang 2025) derives entirely from preclinical models."},{"id":"claim_25","type":"claim","text":"Several clinically important outcomes are represented by only a single study, precluding any within-corpus replication or assessment of consistency. The safety and efficacy of exosomes for knee osteoarthritis, assessed in Bolandnazar 2024 as a randomized, triple-blind, placebo-controlled trial, showed no statistically significant difference between EV-treated and placebo groups for clinical outcomes — yet this single null finding cannot be contextualized against other human trials because no other OA-specific RCT was included. Single-trial findings, whether positive or null, carry substantial uncertainty regarding reproducibility."},{"id":"claim_26","type":"claim","text":"The corpus lacks long-term mortality and hard clinical endpoint data. No included study was designed with long-term survival as a primary endpoint in the aging-relevant population. The mechanism-to-clinic gap therefore remains wide: while preclinical data convincingly demonstrate anti-inflammatory and regenerative properties of EVs (Zhu 2025, Hong 2025), the translation to clinically meaningful, sustained benefit in older adults is not established by the available human evidence."},{"id":"claim_27","type":"claim","text":"For exosomes extracellular vesicles, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support exosomes extracellular vesicles as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_28","type":"claim","text":"This synthesis maps 56 included sources on Extracellular vesicles across 7 outcome classes and 668 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit."},{"id":"claim_29","type":"claim","text":"Across 56 curated reference papers, the evidence base for Extracellular vesicles shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: immune. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Extracellular vesicles anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."},{"id":"claim_30","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the disagreement between Pineiro-Ramil 2025 and Hong 2025 on immune (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"source_1","type":"source","study":"Jafarzadeh 2025","year":2025,"doi":"10.1186/s13287-025-04592-z","url":"https://doi.org/10.1186/s13287-025-04592-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among these, 21% investigated the effects of EVs, while 78% focused on CMs. Reported improvements included a 27.07% increase in skin elasticity ( p < 0.05), over 10% reduction in wrinkles ( p < 0.05), and more than 20% enhancement in hydration ( p < 0.05)."},{"id":"source_2","type":"source","study":"Leung 2025","year":2025,"doi":"10.1186/s12882-025-04196-y","url":"https://doi.org/10.1186/s12882-025-04196-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"There was significant increase in phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) (p = 0.018) in TCMR compared to No TCMR, and similarly when tubulitis (p = 0.037) and interstitial inflammation (p = 0.047) were present. Total inflammation score \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\geq $$\\end{document} 1 was associated with increases in PFKFB2 (p = 0.027), PFKFB3 (p = 0.090) and PFKFB4 (p = 0.0098)."},{"id":"source_3","type":"source","study":"Bolandnazar 2024","year":2024,"doi":"10.1186/s12891-024-07979-w","url":"https://doi.org/10.1186/s12891-024-07979-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment."},{"id":"source_4","type":"source","study":"Wu 2025","year":2025,"doi":"10.1186/s13287-025-04644-4","url":"https://doi.org/10.1186/s13287-025-04644-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results revealed a significant reduction in all-cause mortality among patients receiving MSCs or their derived EVs and secretomes compared to those receiving routine therapy (RR = 0.74, 95% CI = 0.63-0.87, p = 0.0003, I² =5%). This effect was only seen in all-cause mortality within one month (RR = 0.74, 95% CI = 0.62-0.89, p = 0.002, I² =0%); furthermore, high dose MSCs (over 1 × 10 6 cells/kg or 7 × 10 7 cells per infusion) was associated with reduction of all-cause mortality in ARDS (RR = 0.70, 95% CI = 0.55-0.89)."},{"id":"source_5","type":"source","study":"Kishta 2025","year":2025,"doi":"10.1186/s13287-025-04690-y","url":"https://doi.org/10.1186/s13287-025-04690-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For 4 weeks, the first group got weekly topical application of WJ-MSC exosome along with standard of care (SOC); the second control group received SOC alone; and the third placebo group received SOC together with CMC (the exosome vehicle). According to our study’s findings, 53 patients (62%) had fully recovered by the end of the study, and the treated group had a significantly higher percentage of patients who had fully recovered than the control group."},{"id":"source_6","type":"source","study":"Behrangi 2026","year":2026,"doi":"10.1186/s13287-026-05016-2","url":"https://doi.org/10.1186/s13287-026-05016-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Among the included studies, CM was the most extensively investigated therapy (6 studies, 229 patients), showing consistent improvements in hair density (7-16%) and thickness (11-32%), with up to 85% increase in hair count when combined with minoxidil. EV therapy, though less studied (3 studies, 89 patients), showed hair count increases of 28% and density gains up to 45% in certain subgroups, with higher responses in early-stage AGA."},{"id":"source_7","type":"source","study":"Zhu 2025","year":2025,"doi":"10.1186/s12967-024-05744-0","url":"https://doi.org/10.1186/s12967-024-05744-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"sEVs were the most-studies type of EVs ( n = 78), of which 69 nomenclatures were exosome. Other types of EVs include ApoEVs ( n = 5), of which 2 were ApoBDs [ 30 , 31 ], 2 were ApoSEVs [ 32 , 33 ] and 1 was both ApoSEVs and ApoBDs [ 34 ] (Fig."},{"id":"source_8","type":"source","study":"Lu 2025","year":2025,"doi":"10.1186/s13287-025-04432-0","url":"https://doi.org/10.1186/s13287-025-04432-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Pooled analyses demonstrated that exosome improved the nerve conduction velocity [MCV (SMD = 4.71 [2.18;7.25], P = 0.0003; I²= 91.8%), SCV (SMD = 1.07 [0.30;1.85], P = 0.0069; I²= 85.3%)], may restore IENFD [SMD = 1.46 [-0.85; 3.77], P = 0.2164; I²=88.7%], alleviated neuropathic pain [mechanical allodynia (SMD= -0.27 [-1.02;0.47], P = 0.4697; I 2 = 85.0%), thermal hyperalgesia (SMD= -1.48 [-2.45;-0.50], P = 0.003; I 2 = 88.4%)], ameliorated vascular function [blood flow perfusion in plantar (SMD = 2.84 [0.89; 4.80], P = 0.0043; I 2 = 74.9%), blood flow perfusion in sciatic nerves (SMD = 2.62 [0.80; 4.43], P = 0.0047; I 2 = 75.9%), vessel density (SMD = 2.69 [0.90; 4.49], P = 0.0032; I 2 = 0%)], and restored the peripheral nerve structure [sciatic nerve fiber diameter (SMD = 3.29 [1.61; 4.96], P = 0.0066; I 2 = 75.5%), axon diameter (SMD = 2.26 [1.64; 2.88], P < 0.0001; I 2 = 54.3%), myel"},{"id":"source_9","type":"source","study":"Delen 2024","year":2024,"doi":"10.1002/jev2.12458","url":"https://doi.org/10.1002/jev2.12458","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Overall, we have shown that EV‐based therapy is safe with a low incidence of serious adverse events (SAE; 0.7% (95%‐CI: 0.1-5.2%), and adverse events (AE; 4.4% (95%‐CI: 0.7-22.2%). Notably, most studies (12/21, 57%) used differential ultracentrifugation as a method to isolate EVs in the therapeutic product (Figure 2a )."},{"id":"source_10","type":"source","study":"Wang 2025","year":2025,"doi":"10.3389/fphar.2025.1653907","url":"https://doi.org/10.3389/fphar.2025.1653907","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The meta-analysis demonstrated significantly lower SCr levels in exosome-treated animals versus controls (SMD = -5.71, 95% CI: -7.39 to -4.02, P < 0.001; I 2 = 91.60%) ( Figure 2 ; Table 3 ). However, fibroblast-derived exosomes showed no significant SCr reduction versus controls (SMD = -0.76, 95% CI: -1.67 to 0.15, P = 0.101) ( Table 4 )."},{"id":"source_11","type":"source","study":"Zhou 2025","year":2025,"doi":"10.1186/s13018-024-05403-6","url":"https://doi.org/10.1186/s13018-024-05403-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"In total, 1360 articles were identified, of which 17 preclinical studies were based on MSC-derived exosome therapy, and they demonstrated a beneficial effect on BV/TV (SMD = 13.99; 95% Cl = 10.50, 17.48; p < 0.00001), CEJ-ABC (SMD = -0.22; 95% Cl = -0.31, -0.13; p < 0.00001), BMD (SMD = 0.29; 95% Cl = 0.14, 0.45; p = 0.0002), and Tp.Sp (SMD = -0.08; 95% Cl= -0.15, -0.02; p = 0.02) compared with the control group. However, no significant differences were observed in Tp.Th (SMD = 0.03; 95% CI = 0.00, 0.07; p = 0.09) between the exosome-treated group and control group."},{"id":"source_12","type":"source","study":"He 2023","year":2023,"doi":"10.1186/s13287-023-03317-4","url":"https://doi.org/10.1186/s13287-023-03317-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"2 Publication year of the included studies Table 1 Summary of the characteristics of experimental subjects Study Year Experimental subject Model Sex Age Weight Chen 1 2019 Mice OVX-induced osteoporosis model Female - - Chen 2 2019 Mice Senile osteoporosis model Unspecified - - Chen 3 2019 Mice Disuse osteoporosis model (TS-induced osteoporosis model) Unspecified - - Gong 2020 SAMP8 mice Senescence-accelerated model Male 6 months old - Hu 1 2020 C57BL/6 mice OVX-induced osteoporosis model Female 8 weeks old - Hu 2 2020 C57BL/6 mice Senile osteoporosis model Male 16 months old - Hu 3 2020 C57BL/6 mice Disuse osteoporosis model (TS-induced osteoporosis model) Unspecified 3 months old - Huang 2021 SD rats OVX-induced osteoporosis model Female 10 weeks old 230-250 g Li 2021 SD rats OVX-induced osteoporosis model Female 8 weeks old 294 ± 11 g Lu 2020 C57BL/6J mice - Male 3 months old - Qiu 202"},{"id":"source_13","type":"source","study":"Ahmed 2024","year":2024,"doi":"10.1007/s12015-023-10675-2","url":"https://doi.org/10.1007/s12015-023-10675-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"UC and 12% PEG TEM, NTA, WB EVs (50-400 nm) Inhalation 5 doses: 6 ml diluted with normal saline (1.0 × 10 9 haMSCExos per patient) On days 1, 2, 3, 4 and 5 [ 34 ] Mitrani et al. UC NTA, TEM, MACSPlex exosome kit Zofin: EVs and Exosomes (90.2 nm) Intravenous 3 doses: 1 mL diluted in 100 mL of normal saline On days 0, 4, and 8 [ 35 ] Mitrani et al."},{"id":"source_14","type":"source","study":"Dhaliwal 2026","year":2026,"doi":"10.1111/jocd.70881","url":"https://doi.org/10.1111/jocd.70881","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"At baseline the hair density was 158.03/cm 2 and it increased to 166.14/cm 2 ( p < 0.001) at 24 weeks. This was a mean increase of 8.11/cm 2 in 24 weeks."},{"id":"source_15","type":"source","study":"Hong 2025","year":2025,"doi":"10.1007/s12015-025-10852-5","url":"https://doi.org/10.1007/s12015-025-10852-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results of meta-analysis revealed that SC-EVs treatment significantly reduced pancreatic histopathologic scores (total score: MD = -5.17, 95% CI: -5.79, -4.55; inflammation score: MD = -1.44, 95% CI: -1.70, -1.19; edema score: MD = -1.42, 95% CI: -1.75, -1.09; necrosis score: MD = -1.42, 95% CI: -1.80, -1.04), inhibited pro-inflammatory factor release (IL-6: SMD = -3.20, 95% CI: -4.51, -1.88; TNF-α SMD = -5.18, 95% CI: -6.96, -3.40), and enhancing the release of anti-inflammatory factors (IL-10 SMD = 4.15, 95% CI: 2.49, 5.81). While the majority of cases are mild and resolve spontaneously, approximately 15-20% of individuals with AP develop localized and systemic complications, leading to multi-organ failure and even mortality [ 1 , 2 ]."},{"id":"source_16","type":"source","study":"Luo 2024","year":2024,"doi":"10.1186/s13048-024-01489-y","url":"https://doi.org/10.1186/s13048-024-01489-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P < 0.00001; I 2 = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P = 0.0001; I 2 = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P < 0.00001; I 2 = 69%) and counts of different types of follicles. More recently, a global incidence of about 3.7% of women of reproductive age were reported diagnosed with POF/POI [ 1 - 4 ]."},{"id":"source_17","type":"source","study":"Shi 2021","year":2021,"doi":"10.1002/jev2.12134","url":"https://doi.org/10.1002/jev2.12134","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Nebulizing haMSC‐EVs improved survival rate to 80% at 96 h in P. aeruginosa ‐induced murine lung injury model by decreasing lung inflammation and histological severity. Despite management mainly based on supportive measures, such as protective mechanical ventilation, neuromuscular blocking agents or prone positioning, worldwide ARDS mortality remains high, around 30%."},{"id":"source_18","type":"source","study":"Wang 2025b","year":2025,"doi":"10.3389/fphar.2025.1588841","url":"https://doi.org/10.3389/fphar.2025.1588841","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Therefore, a subgroup analysis was performed to reduce the heterogeneity below 50%. I 2 was successfully reduced in each subgroup (MIA: P = 0.40 > 0.05, I 2 = 0% < 50%; DMM: P = 0.47 > 0.05, I 2 = 0% < 50%; ACLT: P = 0.17 > 0.05,I 2 = 44% < 50%; ACLT and DMM: P = 0.13 > 0.05, I 2 = 37% < 50%)."},{"id":"source_19","type":"source","study":"Pineiro-Ramil 2025","year":2025,"doi":"10.1186/s13287-025-04135-6","url":"https://doi.org/10.1186/s13287-025-04135-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The population of isolated particles included a significant proportion (> 20%) of other type of EVs, such as large EVs (> 200 nm). PRISMA flow diagram Summary of selected studies characteristics MSC Medium 5% EV-free FBS Gelatin methacryloyl scaffolds (3D) 2-3 µg/ml (2D) 10-15 µg/ml (3D) CMDs (serum-free) 5 × 10 8 EVs/ml 50 µg/ml MSC Growth/ DMEM/hPL (EV-free) CDM (PPRF-msc6) (serum-free) 3 × 10 8 EVs/ml 1.5 × 10 3 EVs/cell α-MEM serum-free DMEM/F12 15% EV-free human serum DMEM serum-free 2.6 × 10 2 EVs/cell 1.36 µg/10 6 cells DMEM serum-free DMEM serum-free DMEM serum-free MSC Medium serum-free DMEM/F12 10% EV-free FBS α-MEM 10% EV-free FBS α-MEM 5% EV-free hPL DMEM serum-free α-MEM serum-free DMEM/F12 10% EV-free FBS α-MEM 10% EV-free FBS DMEM 10% EV-free FBS CMD (UR51101) (serum-free) DMEM 5% EV-free hPL 1.38 × 10 11 EVs/ml 635 × EVs/cell (OA) 1.12 × 10 11 EVs/ml 709 EVs/cell (healthy"},{"id":"source_20","type":"source","study":"Wei 2026","year":2026,"doi":"10.3389/fbioe.2026.1749916","url":"https://doi.org/10.3389/fbioe.2026.1749916","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Both human- and rat-derived EVs significantly improved all evaluated outcomes, with human-source EVs showing a modest advantage in MRI grading (P = 0.017). When multiple time points were available within this interval, data nearest to 4 weeks were selected for pooled analysis."},{"id":"source_21","type":"source","study":"Zhang 2024","year":2024,"doi":"10.1186/s12890-024-02910-4","url":"https://doi.org/10.1186/s12890-024-02910-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05)."},{"id":"source_22","type":"source","study":"Andrews 2025","year":2025,"doi":"10.1158/1078-0432.CCR-24-3027","url":"https://doi.org/10.1158/1078-0432.CCR-24-3027","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In the pooled cohorts, the median biochemical PFS were 26.1 and 15.0 months ( P = 0.005), and the median radiographic PFS were 36.0 and 25.0 months ( P = 0.003) for PSMA + EV-low and -high groups, respectively. The combination of pre-SABR low levels of both PSMA + EV and PSA was associated with a lower risk of radiographic progression (HR, 0.34, 95% confidence interval, 0.18-0.58; P = 0.0002)."},{"id":"source_23","type":"source","study":"Bozbas 2024","year":2024,"doi":"10.1016/j.ajcnut.2024.03.008","url":"https://doi.org/10.1016/j.ajcnut.2024.03.008","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"PDEV proteome profiles were evaluated, and their impact on coagulation was assessed using assays including fibrin clot formation, thrombin generation, fibrinolysis, and ex vivo thrombus formation. n-3 PUFAs decreased the numbers of circulating EVs by 27%, doubled their n-3 PUFA content, and reduced their capacity to support thrombin generation by >20% in subjects at moderate risk of CVDs. Platelet-derived EVs (PDEVs) comprise the major EV population in the circulation, representing 60%-90% of circulating EVs [ 8 ]."},{"id":"source_24","type":"source","study":"Zhang 2025","year":2025,"doi":"10.3389/fendo.2025.1625969","url":"https://doi.org/10.3389/fendo.2025.1625969","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Specifically, EVs were primarily derived from bone marrow mesenchymal stem cells (BMSCs, n = 10) and human umbilical cord mesenchymal stem cells (n = 2). The most common methods for isolating and purifying EVs are ultracentrifugation (n = 14) and filtration (n = 11), respectively."},{"id":"source_25","type":"source","study":"Zamanian 2024","year":2024,"doi":"10.1002/jev2.12492","url":"https://doi.org/10.1002/jev2.12492","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Besides admission SpO 2 levels, which were significantly lower in the intervention arm ( p = 0.008), all the baseline demo‐biographic and laboratory variables were similar between the groups. It was shown that hPMSC‐sEVs could significantly ( p = 0.015) decrease the mortality ratio in the intervention group (4/21 [19.04%]) compared to the controls (13/24 [54.16%])."},{"id":"source_26","type":"source","study":"Kalluri 2025","year":2025,"doi":"10.1038/s41467-025-63718-2","url":"https://doi.org/10.1038/s41467-025-63718-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Pancreatic ductal adenocarcinoma (PDAC) diagnosis is near uniformly lethal, with a median survival of less than 12 months 1 , 2 , despite the availability of combination chemotherapy regimens. Briefly, exosomes were bound to aldehyde/sulfate beads (10 μl, Life Technologies), saturated with 1 M glycine, washed and blocked with 10% Bovine Serum Albumin (BSA) in PBS."},{"id":"source_27","type":"source","study":"Chernoff 2026","year":2026,"doi":"10.1093/asj/sjaf163","url":"https://doi.org/10.1093/asj/sjaf163","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Pooled analysis revealed superior outcomes compared with control therapies across multiple parameters: Wound healing rate: SMD = 5.42 (95% Cl, 4.40-6.44; P < .00001) I 2 = 73% 9 Neovascular density: SMD = 5.48 (95% Cl, 4.31-6.64; P < .00001) I 2 = 68% 10 Re-epithelialization rate: SMD = 5.06 (95% Cl, 3.75-6.37; P < .00001) I 2 = 71%) 11 Collagen deposition: SMD = 4.78 (95% Cl, 3.58-5.98; P < .00001) I 2 = 69% 12 Scar width reduction: SMD = -8.10 (95% Cl, -10.31 to -5.89; P < .00001) I 2 = 82% 13 The meta-analysis revealed optimal therapeutic windows for exosome intervention. 15 The first of 5 human evidence studies ( NCT02565264 ) evaluated plasma-derived exosomes for chronic wound healing over 28 days."},{"id":"source_28","type":"source","study":"Johnson 2023","year":2023,"doi":"10.1002/jev2.12332","url":"https://doi.org/10.1002/jev2.12332","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Chronic wounds affect 1%-2% of the population in developed world countries, costing more than US$25 billion annually in healthcare (Järbrink et al., 2016 ). The pooled platelet packs were prepared by combining the buffy coats of four ABO identical whole blood donations and resuspending with platelet additive solution (PAS) (MacoPharma, Mouvaux, France) to 70% of the final volume (i.e., 30% buffy coat)."},{"id":"source_29","type":"source","study":"Jeppesen 2025","year":2025,"doi":"10.1038/s41556-025-01621-0","url":"https://doi.org/10.1038/s41556-025-01621-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The cells were seeded and cultured in DMEM medium with FBS depleted for EVs as previously described 53 to 30-50% confluence at 37 °C in a 5% CO 2 humidified incubator. The cell-conditioned medium was collected from MDA-MB-231, Gli36 and B16-F1 cells cultured for 48 h in DMEM with FBS depleted for EVs at 37 °C in a 5% CO 2 humidified incubator."},{"id":"source_30","type":"source","study":"Zhang 2025b","year":2025,"doi":"10.1371/journal.pone.0327011","url":"https://doi.org/10.1371/journal.pone.0327011","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Additionally, for results with significant heterogeneity ( I 2 ≥ 50%), subgroup analyses were conducted based on species (rats/mice), EVs engineering targets/methods, injection frequency, and treatment duration. The isolation methods for BMSC-EVs included ultracentrifugation (N = 7) and precipitation kits (N = 2), while one study did not report the purification details."},{"id":"source_31","type":"source","study":"Santos 2026","year":2026,"doi":"10.3390/ijms27062787","url":"https://doi.org/10.3390/ijms27062787","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Five papers scored above 50% [ 40 , 42 , 43 , 46 , 47 ], three between 40 and 50% [ 41 , 44 , 45 ] and one paper scored lower than 30% [ 48 ]. The highest scoring was 67% due to the robust use of human, murine and cell line models [ 40 ], followed by 61% due to the variety of techniques used to isolate and comprehensively profile EVs [ 42 ]."},{"id":"source_32","type":"source","study":"Ye 2024","year":2024,"doi":"10.3389/fnmol.2024.1448777","url":"https://doi.org/10.3389/fnmol.2024.1448777","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The results indicated that BMSCs-Exo significantly improved the BBB score in SCI rats (WMD = 3.47, 95% CI [3.31, 3.63]), inhibited the expression of the pro-inflammatory cytokine TNF- α (SMD = -3.12, 95% CI [-3.57, -2.67]), and promoted the expression of anti-inflammatory cytokines IL-10 (SMD = 2.76, 95% CI [1.88, 3.63]) and TGF- β (SMD = 3.89, 95% CI [3.02, 4.76]). Additionally, BMSCs-Exo significantly reduced apoptosis levels (SMD = -4.52, 95% CI [-5.14, -3.89]), promoted the expression of axonal regeneration markers NeuN cells/field (SMD = 3.54, 95% CI [2.65, 4.42]), NF200 (SMD = 4.88, 95% CI [3.70, 6.05]), and the number of Nissl bodies (SMD = 1.89, 95% CI [1.13, 2.65]), and decreased the expression of astrogliosis marker GFAP (SMD = -5.15, 95% CI [-6.47, -3.82])."},{"id":"source_33","type":"source","study":"Akhlaghpasand 2024","year":2024,"doi":"10.1186/s13287-024-03868-0","url":"https://doi.org/10.1186/s13287-024-03868-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Following the injection of allogeneic HUC-MSC-exosomes, patients were followed up for 12 months after the study intervention. The multipotency of HUC-MSCs was confirmed through osteogenic and adipogenic differentiation. ( A ) Flow cytometric analysis revealed positive expression of CD29, CD73, CD90, and CD105, while indicating negative expression for CD34 and CD 45 markers in HUC-MSCs. ( B ) The size distribution of exosomes was determined through dynamic light scattering analysis; Mean 63.2 nm, SD: 15.2 nm. ( C ) Transmission electron microscopy images illustrate the structural features of exosomes. (D) Western blot analysis indicated the expression of exosomal surface markers, including CD9 and CD81 (additional file 1 : uncropped blots) The DLS technique was performed to evaluate the size distribution of HUC-MSC-exosomes, and 1 mL of the prepared sample was used for this purpose."},{"id":"source_34","type":"source","study":"Fang 2025","year":2025,"doi":"10.1186/s12931-025-03330-6","url":"https://doi.org/10.1186/s12931-025-03330-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"34 COPD patients participated were treated for 6 months with either placebo or ICS (500 µg fluticasone ± 50 µg salmeterol). An even lower percentage of patients-34%-responded to either ICS/LABA therapy alone [ 5 ]."},{"id":"source_35","type":"source","study":"Kabatas 2025","year":2025,"doi":"10.5492/wjccm.v14.i4.103782","url":"https://doi.org/10.5492/wjccm.v14.i4.103782","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"FIM motor scores improved significantly (46.20 ± 16.39 to 64.20 ± 18.20, P < 0.01), and FIM cognitive scores also showed significant improvement (30.60 ± 4.56 to 34.00 ± 1.41, P < 0.001). While MAS scores improved (right/left: 4.60/3.60 to 2.20/1.60), these changes were not statistically significant ( P > 0.05), possibly due to low baseline spasticity."},{"id":"source_36","type":"source","study":"Grueso-Navarro 2025","year":2025,"doi":"10.3390/ijms26020639","url":"https://doi.org/10.3390/ijms26020639","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"This was a prospective single-center observational study of a discovery cohort of EoE patients ( n = 26) with active disease (EoE.Basal) and after anti-inflammatory treatment (EoE.Post.tx) and control subjects ( n = 16). Plasma EVs (pEVs) were isolated from 1 mL of plasma, thawed at 4 °C, and centrifuged at 5000× g for 30 min to remove protein aggregates and larger EVs. pEVs were purified using size exclusion chromatography (SEC) qEV columns according to the manufacturer’s protocol (Izon, Christchurch, New Zealand)."},{"id":"source_37","type":"source","study":"Habibi 2025","year":2025,"doi":"10.1186/s12886-025-04078-9","url":"https://doi.org/10.1186/s12886-025-04078-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The treatment group ( n = 8 eyes) received 10 µg of MSC-derived exosomes twice daily for two weeks and the control group ( n = 8 eyes) received Phosphate buffered saline(PBS) for their respective eyes. Table S2 provides comprehensive details regarding the clinical outcomes, lacrimal function, and ocular examination for the control and treatment groups at the baseline (before treatment), 2nd weeks (2 weeks’ post-treatment), 4th weeks (4 weeks’ post-treatment), and 12th weeks (12 weeks’ post-treatment)."},{"id":"source_38","type":"source","study":"Wang 2025c","year":2025,"doi":"10.1186/s12967-025-06623-y","url":"https://doi.org/10.1186/s12967-025-06623-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"These data indicate that hUC-MSCs were successfully isolated in vitro and have the ability to differentiate into bone, cartilage, and adipose tissue. ( a ) Flow cytometry analysis of phenotypic marker expression; ( b ) Alizarin red staining (200x): Observation of mineralized nodules after 3 weeks of osteogenic induction (stained red); Safranin O staining (400x): Observation of lipid droplets formed after 3 weeks of adipogenesis (stained orange-red); Alisin blue staining (40x): Observation of chondrogenic spheres formed after 3 weeks of chondrogenic induction (stained blue). ( c ) ALP, Runx2, ACAN, and PPARγ were all well expressed through differentiation induction Exosome (Exos) are nano-sized (50-200 nm) extracellular vesicles produced via the endocytic pathway [ 30 ], and are secreted by many cells in response to their surrounding environment. At the same time, treatment with hUC-MSC-d"},{"id":"source_39","type":"source","study":"Hyun 2025","year":2025,"doi":"10.1002/jev2.70141","url":"https://doi.org/10.1002/jev2.70141","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"ILB‐202 (or placebo) was administered via 2‐hour IV infusions (infusion rate of 250 mL/120 min). ILB‐202 was prepared by aseptically adding 4 mL of ILB‐202 vehicle to an infusion bag containing 250 mL of normal saline."},{"id":"source_40","type":"source","study":"Estupinan 2025","year":2025,"doi":"10.1111/jocd.70208","url":"https://doi.org/10.1111/jocd.70208","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The Exosome Regenerative Complex is created using ExoSCRT technology, which separates and refines 0.1%-0.5% pure exosomes from human adipose stem cells using a two‐step filtration process to remove large particles, cellular debris, proteins, and medium components. Overall skin appearance and dyschromia were not significantly different between the PRP and exosome treatment arms at 6 months."},{"id":"source_41","type":"source","study":"Pan 2025","year":2025,"doi":"10.3389/fphar.2025.1707784","url":"https://doi.org/10.3389/fphar.2025.1707784","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Pooled standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for study outcomes. MSC- sEVs significantly reduced ALT (SMD = -2.49, 95% CI: 3.37, -1.62), AST (SMD = -1.97, 95% CI: 3.32, -0.62), reduced pro-inflammatory cytokines (TNF-α: SMD = -5.23, 95% CI: 7.05, -3.41; IL-6: SMD = -5.00, 95% CI: 7.36, -2.64), and increased survival (OR = 6.11, 95% CI: 2.20-16.98; P = 0.001)."},{"id":"source_42","type":"source","study":"Doi 2025","year":2025,"doi":"10.3390/biom15121663","url":"https://doi.org/10.3390/biom15121663","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Sixty-eight patients with OPD were enrolled, and EVs isolated from 29 patients (13 with chronic obstructive pulmonary disease [COPD], four with COPD and asthma, and 12 with asthma; median age 72 years) were analyzed. Samples were loaded and run with 8 mL of PBS, and the first 1.5 mL was pooled."},{"id":"source_43","type":"source","study":"Niu 2026","year":2026,"doi":"10.3389/fbinf.2025.1690932","url":"https://doi.org/10.3389/fbinf.2025.1690932","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"To control the false-positive rate, the p-values obtained from all hypothesis tests were corrected using the Benjamini-Hochberg method. *p < 0.05 indicated statistically significant difference. In addition, the total concentration of EVs from PRP was nearly 2.77 ± 0.80 × 10 10 particles/mL, and that from activated PRP was nearly 1.10 ± 0.11 × 10 11 particles/mL."},{"id":"source_44","type":"source","study":"Civelek 2024","year":2024,"doi":"10.4252/wjsc.v16.i1.19","url":"https://doi.org/10.4252/wjsc.v16.i1.19","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The protein content of 100 mL vesicles was determined using the BCA protein assay method to confirm the production of MSC-derived exosomes. To examine the characteristics of exosomes, the researchers employed a method where the isolated exosomes were tagged with well-established tetraspanin markers (CD81; 97%, CD9; 79%, and CD63; 95%) ( Supplementary Figure 3 )."},{"id":"source_45","type":"source","study":"Zhu 2022","year":2022,"doi":"10.1186/s13287-022-02900-5","url":"https://doi.org/10.1186/s13287-022-02900-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Our trial shows that a consecutive 5 days inhalation dose of clinical grade haMSC-Exos up to a total amount of 2.0 × 10 9 nano vesicles was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested. Suffering from lower extremities deep venous thrombosis or pulmonary embolism in the past 3 months 14."},{"id":"source_46","type":"source","study":"Li 2025","year":2025,"doi":"10.1038/s41392-025-02262-3","url":"https://doi.org/10.1038/s41392-025-02262-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"When administered via nebulization, hUCMSC-EVs predominantly accumulated in murine lungs and ameliorated bleomycin-induced pulmonary fibrosis, with increased survival rate (from 20% to 80%), restored lung volume, and attenuated injury severity accompanied by elevated oxyhemoglobin saturation and improved pulmonary function evaluations. We took the average body weight of a human as 70 kg and a mouse as 0.025 kg."},{"id":"source_47","type":"source","study":"Su 2024","year":2024,"doi":"10.1016/j.neuroscience.2024.10.018","url":"https://doi.org/10.1016/j.neuroscience.2024.10.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Administration of EVs significantly improved locomotor function as measured by Basso-Beattie-Bresnahan or Basso-Mouse-Scale scores at 1 week (natural EVs: SMD 1.50, 95 % CI 1.06-1.95; bio-engineered EVs: SMD 1.93, 95 % CI 1.34-2.52) and 3 weeks (natural EVs: SMD 2.57, 95 % CI 1.96-3.17; bio-engineered EVs: SMD 3.16, 95 % CI 2.29-4.02) post-injury. EVs also promoted nerve growth (SMD 2.95, 95 % CI 2.12-3.78), enhanced neuron conductivity (MD 0.75, 95 %CI 0.59-0.90), alleviated inflammation (SMD -3.12, 95 % CI -4.15--2.10), and reduced lesion size (SMD -2.90, 95 % CI -3.87--1.93)."},{"id":"source_48","type":"source","study":"Zeng 2025","year":2025,"doi":"10.3389/fimmu.2025.1613716","url":"https://doi.org/10.3389/fimmu.2025.1613716","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Although approximately 80% of acute pancreatitis (AP) cases exhibit a self-limiting course, 20% of patients still progress to moderately severe acute pancreatitis or severe acute pancreatitis (SAP), complicated by systemic inflammatory response syndrome (SIRS) and multi-organ failure, with a mortality rate as high as 39% ( 11 )."},{"id":"source_49","type":"source","study":"Ghanem 2025","year":2025,"doi":"10.3389/fphar.2025.1622280","url":"https://doi.org/10.3389/fphar.2025.1622280","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"DN is typically defined by the presence of chronic kidney disease in a person with diabetes, characterized by persistently elevated levels of albumin in the urine (albumin-to-creatinine ratio ≥30 mg/g) and/or reduced kidney function (eGFR <60 mL/min/1.73 m 2 ) for at least 3 months ( Hoogeveen, 2022 )."},{"id":"source_50","type":"source","study":"Svolacchia 2024","year":2024,"doi":"10.3390/medicina60040670","url":"https://doi.org/10.3390/medicina60040670","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The large number of exosomes that may be lost during the ultrafiltration process is compensated for by an extremely fast, reproducible, painless, and minimally invasive technique since it involves the extraction of only 3.5 mL of adipose tissue, which can provide approximately 6.0 × 10 7 cells with a cell viability of 90% [ 3 , 4 ]. After the first clinical results on the use of 0.20-micron ultrafiltration [ 41 ] using only a physiological saline solution as mechanical support for the 0.2-micron filters, additional patients were enrolled and subjected to a clinical study and using an even higher-purity ultrafiltrate with a solution containing a vial of Skin-B ® 5 mL sterile solution containing amino acids and nonviscoelastic macromolecular hyaluronic acid."},{"id":"source_51","type":"source","study":"Mitra 2026","year":2026,"doi":"10.1002/mnfr.70397","url":"https://doi.org/10.1002/mnfr.70397","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Urinary SF excretion significantly increased post‐intervention ( p < 0.001). A statistically significant overall time‐dependent change in sEV particle concentration was observed following the consumption of both the intervention and the control soups ( p <0.05) (Figure 7A )."},{"id":"source_52","type":"source","study":"Zhong 2023","year":2023,"doi":"10.1186/s13287-023-03409-1","url":"https://doi.org/10.1186/s13287-023-03409-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The exosome size remained basically unchanged after two days of storage at 4 °C, while the exosome size decreased significantly after 3 ~ 4 days. Another study showed that exosomes washed twice with PBS can be stored for 1 ~ 7 days at 4 °C."},{"id":"source_53","type":"source","study":"Vreones 2022","year":2022,"doi":"10.1111/acel.13754","url":"https://doi.org/10.1111/acel.13754","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo‐controlled crossover trial ( NCT02921659 ) of oral NR supplementation (500 mg, 2x /day, 6 weeks)."},{"id":"source_54","type":"source","study":"Dai 2026","year":2026,"doi":"10.1097/MD.0000000000046948","url":"https://doi.org/10.1097/MD.0000000000046948","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Recent 5 years studies have proved that stem cell-derived exosomes possess a broad clinical application in regenerative dentistry by promoting hard and soft tissue regeneration, angiogenesis, nerve repair, and wound healing, inhibiting inflammation and apoptosis, and modulating immune responses."},{"id":"source_55","type":"source","study":"Su 2025","year":2025,"doi":"10.3389/fphar.2025.1617874","url":"https://doi.org/10.3389/fphar.2025.1617874","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The longest time of animal models established in each study was not more than 12 weeks, and there was a lack of long-term study data for comprehensive evaluation."},{"id":"source_56","type":"source","study":"Antoniewicz 2024","year":2024,"doi":"10.1007/s12012-024-09934-6","url":"https://doi.org/10.1007/s12012-024-09934-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"This study initially included 24 healthy male and female occasional tobacco users, defined as consuming no more than 10 cigarettes or 10 pouches of Swedish snus per month, aged between 18 and 40 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candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","screening":{"identified":56,"screened":56,"excluded":0,"included":56,"included_or_retained":56,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"56 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["This paper synthesizes exosomes extracellular vesicles as an aging-related intervention across 56 included source papers and 2834 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 26 adjacent clinical sources, and 3 mechanistic or model-system sources, with 668 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the contextual adjacent evidence outcome class, null signals in the contextual adjacent evidence, safety and comorbidity and skeletal, fracture, and bone outcome classes, and negative signals in the immune outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The conclusion is that exosomes extracellular vesicles should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","7 included sources were assigned to this outcome class. Directional coding: mixed=2, negative=1, null=2, unclear=2. Directness coding: indirect=2, mechanistic=1, review=4.","Several clinically important outcomes are represented by only a single study, precluding any within-corpus replication or assessment of consistency. The safety and efficacy of exosomes for knee osteoarthritis, assessed in Bolandnazar 2024 as a randomized, triple-blind, placebo-controlled trial, showed no statistically significant difference between EV-treated and placebo groups for clinical outcomes — yet this single null finding cannot be contextualized against other human trials because no other OA-specific RCT was included. Single-trial findings, whether positive or null, carry substantial uncertainty regarding reproducibility.","The corpus lacks long-term mortality and hard clinical endpoint data. No included study was designed with long-term survival as a primary endpoint in the aging-relevant population. The mechanism-to-clinic gap therefore remains wide: while preclinical data convincingly demonstrate anti-inflammatory and regenerative properties of EVs (Zhu 2025, Hong 2025), the translation to clinically meaningful, sustained benefit in older adults is not established by the available human evidence.","For exosomes extracellular vesicles, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support exosomes extracellular vesicles as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 56 curated reference papers, the evidence base for Extracellular vesicles shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: immune. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Extracellular vesicles anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nJafarzadeh 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLeung 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBolandnazar 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKishta 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBehrangi 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZhu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDelen 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWang 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZhou 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nHe 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAhmed 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDhaliwal 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nHong 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLuo 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nShi 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWang 2025b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nPineiro-Ramil 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWei 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZhang 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAndrews 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBozbas 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhang 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZamanian 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKalluri 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nChernoff 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nJohnson 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nJeppesen 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhang 2025b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSantos 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nYe 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAkhlaghpasand 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFang 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nKabatas 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGrueso-Navarro 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHabibi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWang 2025c,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHyun 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEstupinan 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPan 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDoi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNiu 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCivelek 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhu 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSu 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZeng 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGhanem 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSvolacchia 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMitra 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhong 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nVreones 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDai 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAntoniewicz 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"3fa5cd13-7439-4f62-b446-2c8e84c03e7e","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Jafarzadeh 2025","doi":"10.1186/s13287-025-04592-z","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Leung 2025","doi":"10.1186/s12882-025-04196-y","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Bolandnazar 2024","doi":"10.1186/s12891-024-07979-w","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Wu 2025","doi":"10.1186/s13287-025-04644-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Kishta 2025","doi":"10.1186/s13287-025-04690-y","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Behrangi 2026","doi":"10.1186/s13287-026-05016-2","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zhu 2025","doi":"10.1186/s12967-024-05744-0","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Lu 2025","doi":"10.1186/s13287-025-04432-0","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Delen 2024","doi":"10.1002/jev2.12458","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Wang 2025","doi":"10.3389/fphar.2025.1653907","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zhou 2025","doi":"10.1186/s13018-024-05403-6","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"He 2023","doi":"10.1186/s13287-023-03317-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Ahmed 2024","doi":"10.1007/s12015-023-10675-2","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Dhaliwal 2026","doi":"10.1111/jocd.70881","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Hong 2025","doi":"10.1007/s12015-025-10852-5","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Luo 2024","doi":"10.1186/s13048-024-01489-y","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Shi 2021","doi":"10.1002/jev2.12134","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Wang 2025b","doi":"10.3389/fphar.2025.1588841","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Pineiro-Ramil 2025","doi":"10.1186/s13287-025-04135-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Wei 2026","doi":"10.3389/fbioe.2026.1749916","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zhang 2024","doi":"10.1186/s12890-024-02910-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Andrews 2025","doi":"10.1158/1078-0432.CCR-24-3027","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Bozbas 2024","doi":"10.1016/j.ajcnut.2024.03.008","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhang 2025","doi":"10.3389/fendo.2025.1625969","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zamanian 2024","doi":"10.1002/jev2.12492","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Kalluri 2025","doi":"10.1038/s41467-025-63718-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Chernoff 2026","doi":"10.1093/asj/sjaf163","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Johnson 2023","doi":"10.1002/jev2.12332","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Jeppesen 2025","doi":"10.1038/s41556-025-01621-0","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhang 2025b","doi":"10.1371/journal.pone.0327011","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Santos 2026","doi":"10.3390/ijms27062787","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Ye 2024","doi":"10.3389/fnmol.2024.1448777","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Akhlaghpasand 2024","doi":"10.1186/s13287-024-03868-0","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Fang 2025","doi":"10.1186/s12931-025-03330-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Kabatas 2025","doi":"10.5492/wjccm.v14.i4.103782","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Grueso-Navarro 2025","doi":"10.3390/ijms26020639","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Habibi 2025","doi":"10.1186/s12886-025-04078-9","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Wang 2025c","doi":"10.1186/s12967-025-06623-y","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Hyun 2025","doi":"10.1002/jev2.70141","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Estupinan 2025","doi":"10.1111/jocd.70208","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Pan 2025","doi":"10.3389/fphar.2025.1707784","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Doi 2025","doi":"10.3390/biom15121663","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Niu 2026","doi":"10.3389/fbinf.2025.1690932","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Civelek 2024","doi":"10.4252/wjsc.v16.i1.19","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhu 2022","doi":"10.1186/s13287-022-02900-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Li 2025","doi":"10.1038/s41392-025-02262-3","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Su 2024","doi":"10.1016/j.neuroscience.2024.10.018","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zeng 2025","doi":"10.3389/fimmu.2025.1613716","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Ghanem 2025","doi":"10.3389/fphar.2025.1622280","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Svolacchia 2024","doi":"10.3390/medicina60040670","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Mitra 2026","doi":"10.1002/mnfr.70397","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhong 2023","doi":"10.1186/s13287-023-03409-1","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Vreones 2022","doi":"10.1111/acel.13754","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Dai 2026","doi":"10.1097/MD.0000000000046948","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Su 2025","doi":"10.3389/fphar.2025.1617874","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Antoniewicz 2024","doi":"10.1007/s12012-024-09934-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"}]}}]}