Extracellular vesicles in wound healing and scar formation: molecular regulation of macrophages, fibroblasts, and their crosstalk.

Extracellular vesicles (EVs) mediate communication between immune and stromal cells during cutaneous repair by transferring proteins, lipids, nucleic acids, and other bioactive components. This review examines their effects on macrophage inflammatory and stress-adaptation programs, fibroblast activation and fate, and macrophage-fibroblast crosstalk in wound healing and pathological scarring. In chronic and metabolically impaired wounds, stem- and stromal-cell EVs commonly reduce persistent inflammation, improve macrophage autophagy and redox balance, and support fibroblast migration, proliferation, survival, and provisional matrix formation. In scar models, some EV preparations attenuate sustained profibrotic and mechanotransduction signaling, whereas EVs from diseased or microenvironmentally conditioned cells can prolong inflammation, maintain myofibroblast activity, and increase collagen deposition. Direct evidence for EV-mediated crosstalk is less extensive than evidence for effects on either cell type alone but supports communication in both directions. Macrophage-derived EVs alter fibroblast metabolism, growth signaling, autophagy, and extracellular matrix (ECM) production through long noncoding RNAs, microRNAs, and chemokines. Fibroblast-derived EVs can coordinate phase-specific macrophage responses during repair, whereas EVs from diabetic ulcers or fibrotic skin may impair macrophage autophagy, activate inflammasome signaling, and reinforce profibrotic feedback. EV activity therefore depends on the state of both donor and recipient cells, the local matrix and metabolic environment, dose, and timing. Particular emphasis is placed on reciprocal EV-mediated macrophage-fibroblast signaling, an aspect of cutaneous repair that remains insufficiently synthesized despite increasing mechanistic evidence. Clinical translation will require causal validation of EV transfer, standardized product characterization, and long-term assessment of wound closure and scar quality.