Supramolecular self‐assembled nanoparticles for targeted therapy of myocardial infarction by enhancing cardiomyocyte mitophagy

Abstract Myocardial infarction accompanied by diabetes mellitus is accepted as the most serious type of coronary heart disease, and among the current treatment strategies, the precise delivery of protective drugs for inhibiting cardiomyocyte apoptosis is still a challenge. In this study, we developed a biodegradable nanoparticles‐based delivery system with excellent macrophage escape, cardiac targeting, and drug release properties to achieve targeted therapy of myocardial infarction. Specifically, a copolymer of p(DMA–MPC–CD) combining self‐adhesion, hydration lubrication, and targeting peptide binding site was successfully prepared by free radical copolymerization, and it was self‐assembled on the surface of melatonin‐loaded dendritic mesoporous silica nanoparticles (bMSNs) following the integration of adamantane‐modified cardiac homing peptide (CHP) based on supramolecular host–guest interaction. Importantly, a hydration layer formed around the zwitterionic phosphorylcholine groups of the multifunctional nanoparticles, which was confirmed by the enhancement in hydration lubrication and reduction in coefficient of friction, prevented the nanoparticles from phagocytosis by the macrophages. The in vivo bioluminescence imaging test indicated that the nanoparticles were endowed with satisfied cardiac targeting capability, and the in vivo mice study demonstrated that the intravenous injection of drug‐loaded nanoparticles (namely bMSNs–Mel@PDMC–CHP) effectively reduced cardiomyocyte apoptosis, alleviated myocardial interstitial fibrosis, and enhanced cardiac function.