Extracellular Vesicle Therapies for Diabetic Skin Lesions: Mechanisms, Engineering, and Clinical Translation.

Diabetic foot ulcers and other chronic diabetic skin lesions persist because vascular insufficiency, neuropathy, infection, oxidative stress, dysregulated inflammation, and impaired stromal and epithelial repair act concurrently. Extracellular vesicles (EVs), including exosome-enriched preparations, can deliver proteins, lipids, and regulatory RNAs to multiple wound-resident cell types and therefore offer a cell-free strategy for this multifactorial pathology. This review examines recent evidence for EV-based therapy across inflammatory resolution, angiogenesis, fibroblast and keratinocyte recovery, extracellular matrix remodeling, redox and mitochondrial homeostasis, and protection from ferroptosis and neutrophil extracellular trap-associated injury. It also evaluates source selection, cargo and surface engineering, and local delivery systems such as hydrogels, dressings, and microneedles. Preclinical studies consistently report improved wound closure and tissue repair, whereas human evidence remains limited to early clinical and biomarker studies. Translation is constrained by product heterogeneity, donor and culture effects, isolation-dependent composition, inconsistent dose metrics, uncertain potency assays, storage and scale-up requirements, and incomplete regulatory alignment. Progress will require phenotype-matched products, MISEV-aligned characterization, GMP-compatible manufacturing, mechanism-linked release assays, and trials that test EVs as adjuncts to high-quality standard care using durable closure and recurrence as clinically meaningful outcomes.