Cell-Free Regenerative Therapies for Wound Healing and Skin Repair: The Emerging Role of Adipose-Derived Stem Cell Extracellular Vesicles

SIGNIFICANCE: Chronic wounds, burns, radiation-injured wounds, and pathological scars remain major clinical challenges despite advances in wound care. Adipose-derived stem/stromal cell extracellular vesicles (ADSC-EVs) offer a cell-free strategy for delivering bioactive proteins, lipids, and nucleic acids across multiple phases of repair, but their clinical value depends on wound-focused product definition, delivery, and evidence standards. RECENT ADVANCES: Preclinical studies consistently associate ADSC-EVs with improved inflammatory control, re-epithelialization, angiogenesis, extracellular matrix remodeling, and scar attenuation. Hydrogels, wound dressings, and microneedle platforms may improve local retention in burns and chronic ulcers. Early human studies in scars and skin aging provide preliminary feasibility and safety signals, whereas evidence in inflammatory dermatoses remains largely preclinical. CRITICAL ISSUES: Products remain heterogeneous in source cells, isolation, characterization, dose metrics, storage, potency testing, and reporting. Many studies use the term "exosome" despite incomplete biogenetic characterization, complicating interpretation and comparison. Outcomes also depend on delivery route and wound context. Human wound-care evidence is limited, and no exosome product has received U.S. Food and Drug Administration approval for routine wound or dermatologic use. FUTURE DIRECTIONS: Translation requires standardized ADSC-EV products, mechanism-linked potency assays, scalable manufacturing compliant with good manufacturing practice, practical wound-specific delivery systems, and indication-specific trials. The greatest opportunities may lie in difficult-to-heal ulcers, burns, radiation-injured wounds, and scar modulation, where multifunctional biological therapies are most needed.[Figure: see text].