Dual‐Targeted Metabolic Nanovesicles Reprogram Macrophage‐Cardiomyocyte Crosstalk for Myocardial Ischemia‐Reperfusion Therapy

Abstract Reperfusion therapy for acute myocardial infarction is limited by myocardial ischemia‐reperfusion injury (MIRI). MIRI is primarily mediated by oxidative stress in cardiomyocytes, exacerbated by M1 macrophages in the inflammatory microenvironment. Synergistic therapies targeting cardiomyocytes with antioxidants and M1 macrophages with anti‐inflammatories have shown significant potential. Mitochondrial dysfunction is a unifying target for both cell types in MIRI; however, current nanoplatforms cannot simultaneously target them. Mito Q@MMNv is designed as a dual‐targeting nanovesicle for cardiomyocytes and macrophages. It scaven​ges reactive oxygen species in cardiomyocytes while restoring oxidative phosphorylation in M1 macrophages through cell‐selective metabolic reprogramming. In vivo, Mito Q@MMNv improves cardiac function and the inflammatory microenvironment: left ventricular ejection fraction increases by 62%, and the M1/M2 ratio shifts (delta cells increase 1.9‐fold). Synergistic activation of Keap1 and inhibition of NF‐κB attenuate inflammatory cascades while enhancing endogenous antioxidant defenses. Thus, this nano‐engineered platform offers an immunomodulatory therapy for inflammation control and tissue repair in MIRI, providing new insights into cardiovascular nanomedicine.