Mitochondrial energy reprogramming via dECM/GP@EVs@Gpnmb to prevent post-myocardial infarction heart failure

Heart failure following myocardial infarction (MI) remains a major cause of mortality. This study aimed to prevent post-MI heart failure by facilitating macrophage mitochondrial transfer through Engineered Extracellular Vesicles-Dextran-Peptide Hydrogel (dECM/GP@EVs@Gpnmb) to induce reprogramming of myocardial mitochondrial energy metabolism. Key macrophage subsets in MI progression were identified using single-cell RNA sequencing data. A mouse model with Gpnmb knockout in macrophages was developed, showing exacerbated myocardial injury. In vitro experiments demonstrated that Gpnmb+ macrophages could transfer “healthy” mitochondria to cardiomyocytes, regulating mitochondrial energy metabolism. The dECM/GP@EVs@Gpnmb promoted a reparative macrophage phenotype, improving mitochondrial energy metabolism in cardiomyocytes and reducing myocardial damage. In vivo , dECM/GP@EVs@Gpnmb treatment enhanced the accumulation of EVs@Gpnmb in infarcted areas, improving cardiac function in MI mice. Overall, this approach holds promise for preventing and treating post-MI heart failure by mediating macrophage mitochondrial transfer and reprogramming myocardial mitochondrial function.