Mitochondria-targeted antioxidant delivery for precise treatment of myocardial ischemia–reperfusion injury through a multistage continuous targeted strategy

Efficient delivery of antioxidant drugs into mitochondria of ischemic cardiomyocytes where reactive oxygen species largely induced is a major challenge for precise treatment of myocardial ischemia–reperfusion injury. Herein, we report a smart dual-shell polymeric nanoparticle, MCTD-NPs, which utilizes multistage continuous targeted strategy to deliver reactive oxygen species scavenger specifically to mitochondria of ischemic cardiomyocytes upon systemic administration. In vitro experiments indicated that the intracellular uptake of MCTD-NPs was specifically enhanced in hypoxia reoxygenation injured H9c2 cells. MCTD-NPs selectively delivered resveratrol to mitochondria of hypoxia reoxygenation injured H9c2 cells. In addition, MCTD-NPs increased the viability of H/R injured H9c2 cell through eliminating mitochondrial ROS, decreasing mPTP opening and blocking mitochondria-dependent apoptotic pathway. In vivo experiments revealed that MCTD-NPs increased the distribution of resveratrol in the ischemic myocardium and subsequently reduced infarct size in MI/RI rats. These results demonstrated a novel platform for specific delivery of antioxidant to mitochondria to treat MI/RI.