Therapeutic Efficacy of Adipose-Derived Extracellular Vesicles in Diabetic Cutaneous Wounds: A Systematic Review of Animal Models

Background: Chronic diabetic cutaneous wounds are sustained by persistent inflammation, impaired angiogenesis, and oxidative stress, with delayed healing. Adipose-derived stem cell extracellular vesicles (ADSC-EVs) act as paracrine mediators and are candidate regenerative therapies. This systematic review synthesized controlled in vivo evidence on ADSC-EVs in diabetic cutaneous wound healing. Methods: PubMed, Embase, Scopus, and Cochrane Library were searched for controlled in vivo studies (publication window 2015 to July 2025; last search 22 October 2026) evaluating ADSC-EVs in diabetic cutaneous wound models. The review followed PRISMA 2020 and was registered in PROSPERO. Methodological quality and reporting were assessed with SYRCLE and CAMARADES. Owing to heterogeneity in models, EV preparation, dosing, delivery, and outcome reporting, the findings were synthesized descriptively. The primary outcome was quantitative macroscopic wound closure, reported as printed numerical values or as planimetric wound-closure trajectories. Results: Nineteen controlled studies met inclusion criteria; all used diabetic rodent wound models. ADSC-EVs were directionally associated with faster wound closure versus vehicle or scaffold-only controls. In six within-study comparisons, hypoxia-preconditioned, circRNA-enriched, or miRNA-enriched vesicles reported greater wound closure than native EVs. Biomaterial carriers were associated with greater closure than free EVs in five studies. The direction of effect was consistent across streptozotocin, high-fat diet plus streptozotocin and db/db models, and across doses of 1 to 200 µg per application, but no study compared models or doses directly. Secondary outcomes included collagen organization, inflammatory markers, and macrophage phenotype. Blinded outcome assessment was reported in one study, and no study reported a sample-size calculation. Conclusions: In preclinical diabetic wound models, ADSC-EVs were consistently associated with enhanced healing across macroscopic and histological endpoints. Heterogeneous reporting and limited blinding preclude effect size estimation. Clinical efficacy, optimal dose, and delivery strategy remain to be established.