Biomimetic peroxisome targets myocardial injury and promotes heart repair and regeneration.

Abstract

Heart ischemic injury predominately causes mitochondrial dysfunction, leading to the accumulation of ROS and lactate. The ROS-associated DNA damage response (DDR) contributes to myocardial cell cycle arrest and the inhibition of proliferation, while lactate accumulation is often accompanied by a high risk of acute death. In this study, to restore myocardial metabolism and regenerate the heart, we established a biomimetic peroxisome by loading the Mn₃O₄ nanozyme into mesenchymal stem cell-derived extracellular vesicles (MSC-EV (Mn@EV)). This setup mimics the peroxidases of peroxisome to catalyze ROS, and inhibit DDR. Next, the Mn@EV was immobilized with lactate oxidase (LOX) after encompassed platelet membrane to obtain biomimetic peroxisome (Mn@LPEV). This mimics the substrate-oxidizing function to detoxify lactate and prevent death. Supported by its biomimetic and lactate-response delivery system, our biomimetic peroxisome effectively targeted deep tissues in the hearts of I/R mice, achieving a 4-fold increase in targeting compared with control vesicles. It maintained myocardial redox homeostasis by scavenging ROS and lactate, inhibiting DDR pathway, promoting myocardial regeneration, reducing acute mortality and fibrosis remodeling, accelerating immunomodulation and angiogenesis, and significantly protecting heart function.