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

Abstract

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.