Abstract
Hepatic ischemia-reperfusion injury (IRI) poses a significant clinical challenge in liver surgery and transplantation, primarily mediated through oxidative stress, mitochondrial dysfunction, and inflammatory activation. Herein, we developed SOD2-Res@CVs, an engineered vesicular platform combining SOD2-overexpressing mesenchymal stem cell-derived vesicles with liver-targeted and ROS-responsive resveratrol (Res)-loaded liposomes for multi-mechanistic intervention. In vivo imaging demonstrated that SOD2-Res@CVs selectively accumulated in IRI-damaged hepatic tissues. Within oxidative stress microenvironments, the system exhibited responsive liberation of SOD2 and resveratrol, which cooperatively mitigated oxidative damage through redox homeostasis modulation - evidenced by reduced lipid peroxidation (MDA suppression) and enhanced antioxidant defense (GSH/SOD2 upregulation). This therapeutic cascade facilitated mitochondrial structural and functional restoration via multiple pathways: Resveratrol specifically activated PINK1-mediated mitophagy, as confirmed by increased LC3 and beclin-1 expression, thereby promoting selective clearance of depolarized mitochondria. Comparative analyses revealed SOD2-Res@CVs' superior therapeutic efficacy over individual components in histological recovery and organ function preservation. Transcriptomic profiling further validated the system's multi-target regulatory capacity, highlighting its concurrent suppression of oxidative stress pathways, mitigation of inflammatory signaling, and improvement of mitochondrial bioenergetics during IRI progression. This study establishes SOD2-Res@CVs as a multifunctional nanotherapeutic strategy that harmonizes spatial targeting with pathological microenvironment responsiveness and a promising approach for liver protection in transplantation.