Nanotherapy‐Engineered Stem Cells Alleviate Myocardial Reperfusion Injury by Normalizing the Pathological Microenvironment and Promoting Cardiac Repair

Abstract Myocardial infarction, the most severe manifestation of coronary artery disease, is a leading cause of mortality worldwide. Here, a novel nanotherapy engineering approach is reported for enhancing therapeutic effects of mesenchymal stem cells (MSCs) on myocardial ischemia‐reperfusion (MI/R) injury. An anti‐oxidative and anti‐inflammatory nanotherapy (TPCD NP) is first fabricated. MSCs are successfully engineered with TPCD NP by endocytosis, and TPCD NP engineering does not affect stemness of MSCs. TPCD NP‐internalized MSCs (tn‐MSCs) are resistant to oxidative stress, cytotoxicity, and apoptosis induced by reactive oxygen species (ROS). Under oxidative distress, tn‐MSCs show stronger paracrine activity compared to MSCs. Consistently, tn‐MSCs effectively enhance angiogenesis of endothelial cells under pathological conditions. Also, tn‐MSCs protect cardiomyocytes from ROS‐induced cytotoxicity and apoptosis by improving mitochondrial membrane potential and regulating the p53 signaling pathway. In mice with MI/R injury, the survival time of tn‐MSCs in the injured heart is prolonged, compared to pristine MSCs. Correspondingly, tn‐MSCs more significantly reduce the infarct size, improve cardiac function, and promote cardiac remodeling in MI/R injury mice. Mechanistically, tn‐MSCs alleviate MI/R injury by attenuating oxidative stress and inflammation, inhibiting cardiomyocyte apoptosis, and promoting cardiac repair. Consequently, tn‐MSCs are promising for treating cardiovascular diseases linked to oxidative distress and inflammation.