Stem cell-derived nanovesicles delivered by responsive hydrogels for refractory wound therapy

Abstract

The dynamic microenvironment of refractory wounds comprises a complex pathological system characterized by interconnected factors, such as persistent infection, chronic inflammation, and impaired tissue repair. These pathological cues substantially hinder the healing process and negatively impact patients' quality of life. Stem cell-derived nanovesicles (SC-NVs) offer a variety of reparative functions, including antimicrobial activity, immunomodulation, angiogenesis, enhanced cellular proliferation and migration, and scarless healing, thereby demonstrating substantial potential for tissue regeneration. However, topical administration of nanovesicles is limited by poor tissue retention and rapid clearance, which constrain therapeutic efficacy and necessitate repeated dosing. Hydrogels, by virtue of their excellent biocompatibility, high water content, and tunable physicochemical properties, represent promising drug delivery vehicles. This review systematically examines the microenvironmental features of refractory wounds and the therapeutic mechanisms of SC-NVs in counteracting them to promote healing. Notably, nanovesicles can be loaded by smart hydrogel systems to respond to wound microenvironmental cues and allow for on-demand release via dynamic bond cleavage or structural transformation, thereby augmenting therapeutic precision. Finally, we discuss key challenges in the clinical translation of these integrated platforms and outline their future applications in precision diagnostics and therapeutics for refractory wounds.