Extracellular vesicles from honokiol-enhanced human induced pluripotent stem cell-derived cardiomyocytes promote cardiac repair through macrophage metabolic reprogramming

Macrophage-mediated inflammatory immune environment drives adverse consequences after myocardial infarction (MI), such as heart failure. Induced pluripotent stem cell-derived cardiomyocytes (iCMs) exert therapeutic effects in MI treatment through paracrine mechanisms. This study investigated the role of extracellular vesicles and the underlying mechanism from iCMs treated with honokiol (HKL) in ameliorating the inflammatory microenvironment post-MI. Here, we reported that HKL pretreatment enriched iCM-EVs with functional mitochondria. iCM HKL -EVs administration markedly improved cardiac function and reduced inflammation in MI mice, which was associated with a shift in macrophages towards an anti-inflammatory M2 phenotype. In vitro , iCM HKL -EVs transfer mitochondria to macrophages, promoting M2 polarization and efferocytosis. Mechanistically, internalization of mitochondria from iCM HKL -EVs enhanced tethering between mitochondria and lipid droplets in macrophages, in a CPT1A-dependent manner, accompanied by enhanced CPT1A/Rab18 interaction, and subsequently led to an improved macrophage inflammatory response through facilitating lipid droplet consumption and fatty acid metabolism. Our study demonstrates that optimizing iCM-EVs with HKL creates a novel cell-free therapy that ameliorates MI injury by transferring mitochondria to macrophages. This strategy highlights the therapeutic potential of manipulating donor cell metabolism to enhance EV-based treatments for MI.