Extracellular vesicles from mesenchymal stem/stromal cells as emerging tools in wound healing: mechanisms and...

Wound healing in adult mammals is a regulated but imperfect process in which fibrotic repair dominates over proper regeneration. Mesenchymal stem/stromal cells (MSCs) are considered promising in regenerative medicine; however, evidence suggests that their benefits are primarily mediated by paracrine signaling, including the secretion of extracellular vesicles (EVs). We conducted a structured review to evaluate the potential of MSC-derived EVs (MSC-EVs) in wound management. PubMed was searched for original studies published between January 2015 and July 2025. Of 171 records, 19 met the inclusion criteria. The data included the MSC source, EV isolation, dosing, and effects on wound repair. The review is organized into six themes. First, MSC-EVs consistently promoted the proliferation and migration of keratinocytes, fibroblasts, and endothelial cells, enhancing wound closure in vitro and in vivo. Second, pro-angiogenic effects were evident, often mediated through the PI3K/AKT/mTOR/HIF-1α signaling pathway, although tissue-specific responses were observed. Third, MSC-EVs exhibit immunomodulatory activity by reducing pro-inflammatory cytokines, inducing M2 macrophage polarization, and improving outcomes in chronic and diabetic wound models. Fourth, in extracellular matrix (ECM) remodeling, MSC-EVs increased collagen synthesis, regulated metalloproteinases, and reduced scar formation. Fifth, strategies such as MSC preconditioning and hydrogel-based delivery enhanced EV stability, prolonged activity, and improved therapeutic efficacy. Finally, we assessed methodological challenges, including heterogeneity in EV isolation and characterization, inconsistent dosing, limited adherence to ISCT and ISEV standards, and a lack of GMP-compliant protocols. In summary, MSC-EVs emerge as multifaceted acellular therapeutics that influence key phases of wound repair, including cell activation, angiogenesis, immune modulation, and ECM remodeling. They hold promise for accelerating healing and reducing fibrosis. However, substantial barriers remain before clinical translation, particularly the standardization of EV preparation and regulatory compliance. Addressing these gaps is essential for advancing MSC-EVs into safe, effective, and scalable therapies for wound healing.