**Background:** Skin wounds are common injuries that impose a significant socioeconomic burden. Wound healing is a complex process involving hemostasis, inflammation, proliferation, and remodeling. Traditional therapies (e.g., dressing changes, skin grafting) are often slow and infection-prone. Mesenchymal stem cells (MSCs) have shown promise in regenerative medicine, but cell-based therapies face issues like host rejection. MSC-derived extracellular vesicles (EVs) offer a cell-free alternative with lower immunogenicity, higher stability, and the ability to carry bioactive molecules. This review provides a comprehensive overview of the roles, mechanisms, and clinical potential of MSC-derived EVs in wound repair.
**Methods:** This is a narrative review that synthesizes findings from preclinical studies (in vivo and in vitro) and early clinical trials. The authors discuss the biological properties of MSCs and EVs, the mechanisms of EV action in wound healing (including signaling pathways), and strategies to enhance EV efficacy through pretreatment, engineering, and combination with biomaterials. They also summarize current limitations and future perspectives.
**Key Results:** MSC-derived EVs promote wound healing through multiple mechanisms: (1) accelerating hemostasis via procoagulant effects; (2) modulating inflammation by inducing M2 macrophage polarization and reducing proinflammatory cytokines (e.g., TNF-α, IL-6, IL-8); (3) enhancing cell proliferation and angiogenesis through miRNAs (e.g., miR-126, miR-21-3p) and proteins (e.g., VEGF, FGF); (4) inhibiting scar formation by regulating ECM remodeling (e.g., increasing MMP-3/TIMP-1 ratio, reducing TGF-β1/Smad2/3 signaling). Key signaling pathways include PI3K/Akt/mTOR, TGF-β/Smad, Wnt/β-catenin, and Rho/ROCK/YAP. Pretreatment of MSCs (e.g., hypoxia, cytokines, biochemicals) can enhance EV efficacy. Engineered EVs (surface/internal modifications) and EV-mimetic nanovesicles (NVs) improve targeting and yield. Combination with biomaterials (e.g., hydrogels, 3D bioprinted scaffolds) enables sustained release and multifunctional wound management. Clinical trials (e.g., NCT02565264, NCT05078385) are ongoing for chronic ulcers and burns, with early safety and efficacy data.
**Clinical Implications:** MSC-derived EV therapy holds significant promise for treating acute and chronic wounds, including diabetic ulcers and burns, by promoting regeneration and reducing scarring. However, challenges remain: lack of standardized production and purification protocols, variable EV composition, low yield, and unknown long-term safety (e.g., carcinogenicity). Future work must establish quality control standards, optimize isolation methods, clarify pharmacokinetics, and conduct rigorous clinical trials to translate EV-based therapies into routine clinical practice.