Extracellular vesicle-integrated core-shell nanofibers synergize multi-target healing mechanisms for accelerated repair of large-volume skin defects.

Large-volume skin defects, such as diabetic ulcers and burns, pose a significant clinical challenge due to impaired healing capacity and a lack of effective treatment options. Although mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are well-established promoters of angiogenesis in wound healing, their multi-mechanistic regulatory networks and functionalities when integrated with biomaterials are not fully elucidated. In this study, we developed a core-shell polycaprolactone/gelatin nanofiber scaffold incorporating bone marrow MSC-EVs (PCL-EVs). The incorporation of PCL-EVs enhanced the scaffold's hydrophilicity, which in turn facilitated cell adhesion and proliferation. Functionally, the PCL-EVs scaffold suppressed pro-inflammatory cytokine release, enhanced endothelial tubule formation, promoted fibroblast lipid catabolism, and increased mitochondrial abundance. Mechanistically, PCL-EVs mediated angiogenesis through upregulation of HIF-1α-VEGF signaling and cGMP-PKG cascades. Furthermore, PCL-EVs modulated inflammatory responses by inhibiting the PANoptosis pathway, leading to a reduction in pro-inflammatory cytokines. In fibroblasts, PCL-EVs induced metabolic reprogramming characterized by increased lipolysis and mitochondrial biogenesis, thereby boosting ATP and metabolite production to support tissue repair. In a rat large full-thickness excisional wound splinting model, the PCL-EV nanofiber scaffold demonstrated significant potential for remodeling skin defects. This study not only developed a biomimetic core-shell scaffold as a sustained-release platform for MSC-EVs but also elucidated the mechanisms through which it promotes full-thickness wound healing, demonstrating its multi-faceted role in enhancing angiogenesis, immunomodulation, and metabolic reprogramming.