Citrus sinensis (L.) Osbeck-Derived Extracellular Vesicle-Loaded Hydrogel Dressing Accelerates Wound Healing

Abstract

Wound healing is a multifaceted physiological process encompassing hemostasis, inflammation, cell proliferation, and tissue remodeling. However, the clinical management of chronic wounds remains a major therapeutic challenge. In this study, a light-curable gelatin methacrylate (GelMA) hydrogel encapsulating Citrus sinensis (L.) Osbeck-derived extracellular vesicles (CSEVs) was developed, and its biological properties and wound-healing efficacy were systematically evaluated through in vitro experiments using L929 fibroblasts and RAW264.7 macrophages, as well as an in vivo full-thickness skin defect model in SD rats. The results demonstrated that the CSEV-loaded GelMA hydrogel exhibited negligible cytotoxicity while significantly promoting L929 cell viability and migration and RAW264.7 macrophage polarization. In vivo findings further revealed that, compared with the control group, SD rats with CSEVs treatment showed accelerated wound closure, improved tissue architecture, reduced inflammatory cell infiltration, enhanced neovascularization, and more organized and abundant collagen deposition. Mechanistically, the gelatin-based hydrogel serves as a stable delivery platform for extracellular vesicles, providing a supportive microenvironment that facilitates cellular activities. By modulating inflammatory responses, enhancing cell function, and promoting collagen synthesis, the CSEV-loaded GelMA system effectively accelerates skin wound repair. Overall, this study provides insights and a solid experimental foundation for the development of advanced biomaterial-based strategies in skin tissue regeneration.