Immune disorders are intimately involved in the pathological progression of myocardial ischemia-reperfusion injury (MIRI) and exacerbate cardiac cell damage and mitochondria-related metabolic abnormalities. However, low-immunogenic therapeutic strategies targeting the compromised immune-metabolic microenvironment remain a major challenge. Here, we developed a syngenic reparative macrophage system for the selective delivery of nanoscale drugs by modifying liposomes loaded with nano-Pt/Se and c176 onto the surface of M2 macrophages (PS-c@M). In MIRI mice, transplanted PS-c@M was actively recruited to the myocardial ischemic region, maintained long-lasting residence, and responsively released surface-loaded nanomedicines, which in turn synergistically promoted cardiac cell survival and activated extracellular repair and angiogenesis, thus exerting long-term cardioprotective effects. Specifically, PS-c@M significantly inhibited STING-related signaling pathways, thereby remodeling the immune-inflammatory homeostasis, as evidenced by the increased proportions of M2 macrophages, reparative cardiac resident macrophages, and regulatory T cells and the decreased recruitment and infiltration of M1 macrophages and neutrophils. Moreover, PS-c@M facilitated mitochondrial oxidative phosphorylation and suppressed mitochondria-associated ferroptosis and oxidative damage. This study highlights a low-immunogenic targeted therapeutic strategy based on syngenic reparative macrophages as efficient nanomedicine carriers, with potential for development and application in a wide range of immune and inflammation-related diseases.
Keywords: extracellular environment; immune-inflammatory homeostasis; mitochondrial metabolism; myocardial ischemia–reperfusion injury; nanoengineered macrophages.