Bioinspired Spatiotemporal‐Responsive Nanoparticles Synergistically Regulate Mitochondrial Repair and Inhibit Fibrosis in Acute Myocardial Infarction Treatment

ABSTRACT Cardiovascular diseases, particularly acute myocardial infarction (AMI), have posed a significant global health burden due to the high morbidity and mortality rates. Current treatment methods are compromised by a narrow therapeutic window, risk of ischemia‐reperfusion injury, rapid systemic drug clearance, and inadequate targeting efficiency. To address these limitations, we developed an innovative multifunctional biomimetic nano‐therapeutic system (PDMC/CHP@S/V), which comprised a triblock copolymer synthesized through controlled polymerization of dopamine methacrylamide (DMA), 2‐methacryloyloxyethyl phosphorylcholine (MPC), and methacrylate‐functionalized cyclodextrin. Adamantane‐conjugated cardiac homing peptide was anchored onto the nanoparticles surface via host‐guest interactions, enabling precise infarct‐targeting drug delivery. The cell membrane‐like MPC shell markedly reduced macrophage‐mediated phagocytosis, prolonging circulation time, while the catechol groups in DMA provided robust antioxidant effects by scavenging reactive oxygen species (ROS). The in vitro experiments showed that the nanosystem effectively reduced ROS level, alleviated cell apoptosis, and restored mitochondrial membrane potential in hypoxic cardiomyocytes. Furthermore, the in vivo tests indicated that PDMC/CHP@S/V significantly improved cardiac function, as evidenced by a remarkable reduction of myocardial fibrosis and attenuated ventricular remodeling in AMI mice model. Collectively, the spatiotemporal collaborative delivery design of PDMC/CHP@S/V nanoparticles addressed limitations of conventional therapies, providing an efficient, stable, and safe strategy for achieving targeted AMI treatment.