ApoEVs@FeSe₂-RGD as a synergistic redox-immune regulator for accelerating wound healing

Wound healing still faces many significant challenges, such as excessive oxidative stress, persistent inflammation and disrupted angiogenesis. To overcome these obstacles, we developed a biomimetic hybrid regulatory platform (ApoEVs@FeSe₂-RGD) by anchoring redox-active FeSe₂ nanorods onto mesenchymal stem cell-derived apoptotic extracellular vesicles (ApoEVs), followed by surface functionalization with cyclic RGD (cRGD) peptides. This regulator effectively synergizes the robust reactive oxygen species (ROS)-scavenging capacity of FeSe₂ with the exceptional biocompatibility of cRGD-functionalized ApoEVs. In vitro assessments revealed that ApoEVs@FeSe₂-RGD efficiently cleared abnormally produced ROS to recalibrate the oxidative microenvironment. Consequently, it inhibited pro-inflammatory activation while driving macrophage polarization toward an anti-inflammatory phenotype. The reparative cytokines derived from these reprogrammed macrophages significantly enhanced the migration, proliferation, and angiogenic capacity of endothelial cells. Furthermore, the in vivo assessments in a full-thickness wound healing model demonstrated that this vesicle-scaffolded regulator enhanced the wound closure rate and promoted re-epithelialization, collagen deposition, and neovascularization with good biosafety. Mechanistically, transcriptomic profiling combined with protein validation demonstrated that these therapeutic effects were mediated by the suppression of the NF-κB signaling pathway. Collectively, our study demonstrated that ApoEVs@FeSe₂-RGD holds potential as a therapeutic strategy for wound healing by restoring redox homeostasis and orchestrating immune-vascularization coupling for high-quality tissue regeneration.