FNDC5/irisin-loaded apoptotic nanovesicles encapsulated in photo-crosslinkable PRF-GEL accelerate diabetic wound healing by promoting efferocytosis

• Engineered apoVIs: Developed FNDC5/irisin-overexpressing apoptotic nanovesicles (apoVIs) for targeted delivery. • Key apoVI Mechanisms: apoVIs enhance efferocytosis, drive M2-polarization, and suppress efferocytosis-defect-induced inflammation. • PRF-GEL: a stable hydrogel for sustained apoVI delivery, enhancing stability & tunability while preserving PRF's bioactivity and 3D structure. • PRF-GEL@apoVIs promotes diabetic wound healing in db/db mice by enhancing efferocytosis and M2 macrophage polarization, thereby reducing inflammation and accelerating closure. Persistent inflammation in diabetic skin wounds poses significant therapeutic challenges. Fibronectin domain-containing protein 5 (FNDC5), or its cleaved form irisin, is an exercise-induced myokine with anti-inflammatory activity. However, its effect on skin wound repair remains unclear. FNDC5/irisin-overexpressing mesenchymal stem cell-derived apoptotic nanovesicles (apoVIs) were generated. A gelatin methacryloyl (GelMA)/platelet-rich fibrin (PRF) composite hydrogel encapsulating the engineered apoVIs, termed PRF-GEL@apoVIs, was developed for the sustained release of apoVIs. Their effects on macrophage-related inflammation were evaluated in vitro and in vivo. Priming bone marrow-derived macrophages with apoVIs promoted macrophage recruitment, efferocytosis, M2 polarization and attenuated inflammatory response resulting from efferocytosis defects. The initial PRF scaffold was effectively stabilized and preserved upon rapid centrifugation of the GelMA precursor solution and whole blood mixture. Following UV crosslinking, the composite hydrogel demonstrated superior stability and sustained-release capabilities of apoVIs. In db/db mice, PRF-GEL@apoVIs significantly accelerated wound closure, enhanced granulation tissue formation, collagen deposition, and angiogenesis, promoted clearance of apoptotic neutrophils, and increased M2 macrophage polarization. The PRF-GEL@apoVIs system promotes resolution of inflammation and tissue repair in diabetic wounds by enhancing efferocytosis and modulating macrophage phenotype, representing a promising therapeutic strategy for chronic diabetic wounds.