Conclusion

In summary, we successfully developed MQgel@Mito, a robust platform for mitochondrial protection and transplantation that overcame the fundamental viability constraints limiting current MTT approaches. In vitro, MQgel protected donor mitochondria from oxidative stress and calcium overload in the transplantation environment, facilitating the survival and function of mitochondria. MQ promoted the internalization of donor mitochondria by macrophages via an AMPK-dependent macropinocytic mechanism. Furthermore, MQ@Mito modulated the polarization of macrophages by metabolic reprogramming and attenuated apoptosis by maintenance of mitochondrial homeostasis and weakened oxidative stress. In vivo, we confirmed that MQgel@Mito improved the efficacy of MTT, markedly improving cardiac function and inhibiting the pathological adverse remodeling post-MI. By supplying more functional donor mitochondria to the infarct border zone and exerting the metabolic effect of MQgel, MQgel@Mito achieved therapeutic effects substantially exceeding those of either component alone with the weakest inflammatory response and cardiac damage. The demonstration that macrophage immunometabolism can be therapeutically targeted to promote cardiac repair opens new avenues for regenerative medicine beyond the cardiovascular system. As mitochondrial dysfunction underlies diverse pathologies, including neurodegenerative diseases, metabolic disorders, and inflammatory conditions, the principles established here may find broad application across therapeutic domains. This integrated platform substantially improves cardiac function and limits pathological remodeling in rats, highlighting the therapeutic potential of targeting macrophage immunometabolism in regenerative medicine. Given that mitochondrial dysfunction underlies many diseases, the principles established here may extend beyond cardiovascular repair.