Extracellular vesicles in chronic wound therapy: engineering strategies and advanced delivery systems for enhanced regeneration

Chronic wounds, including diabetic foot ulcers, are notoriously difficult to heal due to their complex pathological microenvironments, which are marked by persistent inflammation and impaired angiogenesis. These challenges place a significant burden on both patients and healthcare systems. Extracellular vesicles (EVs), as natural carriers, can modulate the wound microenvironment and facilitate tissue regeneration by delivering bioactive molecules such as proteins and nucleic acids. EVs offer advantages including low immunogenicity and excellent biocompatibility. However, unmodified EVs face limitations such as low therapeutic payloads, limited targeting capability, and vulnerability to degradation. Building on this foundation, this review provides a detailed overview of the specific roles and mechanisms of EVs in wound healing. It focuses particularly on condition-specific strategies, engineering approaches, and the use of biomaterials to further enhance the therapeutic efficacy of EVs in treating chronic wounds. Finally, we highlight the current challenges faced in the clinical translation of EV-based therapies and propose emerging strategies to address these obstacles, offering new directions for chronic wound management.