Mitochondria-derived peptide hydrogel enhances mitochondrial transplantation and promotes cardiac repair through macrophage metabolic reprogramming

Background Acute myocardial infarction (AMI) is characterized by excessive oxidative stress, persistent inflammation, and profound mitochondrial dysfunction. Although mitochondrial transplantation therapy (MTT) has emerged as a promising strategy to restore cellular bioenergetics, its clinical translation is severely limited by the extreme fragility and rapid functional deterioration of isolated mitochondria. Mitochondrial Open Reading Frame of the 12S rRNA Type-C (MOTS-c), a recently identified mitochondria-derived peptide (MDP), exerts intrinsic mitochondrial protective effects. Purpose We aimed to develop an MDP-based hydrogel capable of protecting and delivering donor mitochondria in vitro and within the hostile post-infarction microenvironment in vivo, thereby enhancing the therapeutic effect of MTT for AMI. Methods Inspired by the intrinsic cellular defense mechanisms against mitochondrial dysfunction, we conjugated MOTS-c with the self-assembling peptide Q11 to construct a co-assembled hydrogel platform (MQgel) for mitochondrial encapsulation and delivery (MQgel@Mito). The functional viability and enzymatic activity of isolated mitochondria were assessed in vitro to evaluate the protective capacity of MQgel. In macrophages, mitochondrial internalization, metabolic reprogramming, polarization status, mitochondrial homeostasis, and apoptosis under oxidative stress were systematically investigated. Therapeutic efficacy was further examined in a rat AMI model. Results MQgel significantly prolonged mitochondrial survival and preserved metabolic enzyme activity for more than 8 hours. The hydrogel not only shielded donor mitochondria from oxidative stress and calcium overload, but also enhanced mitochondrial internalization by macrophages via an adenosine 5'-monophosphate-activated protein kinase (AMPK)-dependent mechanism. MQgel@Mito suppressed glycolysis-associated pro-inflammatory metabolism and promoted oxidative phosphorylation, thereby facilitating macrophage metabolic reprogramming and attenuating M1 polarization. Additionally, MQgel@Mito maintained mitochondrial homeostasis, reduced reactive oxygen species generation, and mitigated macrophage apoptosis under stress conditions. In vivo, treatment with MQgel@Mito inhibited M1 macrophage infiltration, alleviated cardiomyocyte injury, improved cardiac function, and attenuated adverse remodeling after AMI. Conclusion MQgel effectively enhances mitochondrial transplantation by preserving donor mitochondrial viability and functionality. The protective mitochondrial delivery platform MQgel@Mito attenuates macrophage-driven inflammation through metabolic reprogramming and exerts significant therapeutic benefits in cardiac repair following AMI.