Empowering Extracellular Vesicle Wound Therapy via Local Drug Delivery Systems: Mechanistic Insights and Advanced Stimuli-Responsive Strategies

Extracellular vesicles have emerged as promising cell-free therapeutic agents for wound healing due to their remarkable ability to modulate inflammatory responses, promote angiogenesis, and enhance tissue regeneration. These biological nanocarriers deliver bioactive cargo, including regulatory miRNAs, proteins, and lipids, to recipient cells, thereby modulating key signaling pathways governing tissue repair. However, the clinical translation of extracellular vesicle (EV)-based therapies is substantially limited by challenges in delivery efficiency. Local drug delivery systems (LDDSs) offer several key advantages, including reduced clearance by the reticuloendothelial system, enhanced biodistribution to wound sites, prolonged local residence time, and precise spatial targeting of therapeutic effects. This review systematically summarizes recent advances in EV-based therapies for wound repair, with a particular focus on in situ forming and implantable LDDSs, such as stimuli-responsive hydrogels. We comprehensively discuss the molecular and cellular mechanisms through which EVs facilitate healing across all phases of wound repair. Furthermore, we critically evaluate the evolution of these delivery platforms, transitioning from conventional passive-release systems to advanced stimuli-responsive hydrogels and microneedle systems, assessing their design rationale and integration with EV biology. We also address key translational challenges and opportunities: scalable manufacturing, standardized quality control, and regulatory pathways, offering a forward-looking view on clinical implementation of EV-LDDS hybrids in precision regenerative therapy.