Macrophage exosome-modified Mn/Se nanoheterostructure induces post-infarction cardiomyocyte regeneration and immunometabolic microenvironment repair

Myocardial infarction (MI) is the most lethal cardiovascular disease and poses a critical threat to global health. While current MI therapies partially improve cardiac function, advanced precision therapies with translational potential capable of interrupting the vicious pathological cycles remain a pivotal challenge to be addressed. Here, based on a Mn/Se nanoheterostructure that meets human elemental requirements, we constructed a PMS@ME nanotherapeutic system for achieving efficient post-MI repair. Polydopamine was incorporated to synergistically enhance biocompatibility and therapeutic efficacy. The surface is modified with exosomes derived from macrophages that highly express adhesion receptors, enabling precise targeting to the myocardial injury area. PMS@ME administration promotes cardiomyocyte survival, extracellular repair, and mitochondrial homeostasis, while suppressing oxidative damage and immune-inflammatory disorders, achieving preserved cardiac function. Importantly, PMS@ME can induce cardiomyocyte to restart the cell cycle and promotes post-MI cardiomyocyte regeneration by inhibiting the Hippo signaling pathway. These findings demonstrate the potential of the PMS@ME system in MI treatment, offering a blueprint for designing multifunctional nanotherapies tailored to human elemental essentials.