Mitochondria-derived peptide hydrogel augments mitochondrial transplantation for promoting cardiac repair via macrophage metabolic reprogramming

Myocardial infarction (MI) is characterized by severe oxidative stress, excessive inflammation, and profound mitochondrial dysfunction. Although mitochondrial transplantation offers therapeutic promise for MI, its clinical translation is severely hampered by the extreme fragility of donor mitochondria with rapid loss of functional viability after isolation. Here, inspired by the intrinsic cellular defense mechanisms against mitochondrial dysfunction, MOTS-c, a mitochondria-derived peptide (MDP), is selected and further conjugated with self-assembling peptide (Q11) to fabricate a hydrogel-based mitochondrial delivery system (MQ gel @Mito) for cardiac repair after MI. It has been observed that MQ gel significantly extends the survival of isolated mitochondria and maintains metabolic enzyme activity for at least 8 h. More importantly, MQ gel not only shields donor mitochondria from oxidative stress and calcium overload, but also enhances mitochondrial internalization by macrophages through an adenosine 5′-monophosphate-activated protein kinase (AMPK)-dependent mechanism. Furthermore, MQ gel @Mito facilitates metabolic reprogramming of macrophages by suppressing pro-inflammatory glycolysis and enhancing oxidative phosphorylation (OXPHOS), thereby attenuating M1 polarization. Additionally, MQ gel @Mito maintains mitochondrial homeostasis, reduces reactive oxygen species (ROS), and rescues apoptosis of macrophages. In a rat MI model, MQ gel @Mito reduces M1 macrophage infiltration and cardiomyocyte damage by delivering viable mitochondria, thereby improving cardiac function and limiting pathological remodeling. These findings establish a paradigm for mitochondrial protection and demonstrate macrophage immunometabolism as a viable therapeutic strategy for MI.