Bioenergetic Metabolism Modulatory Peptide Hydrogel for Cardiac Protection and Repair After Myocardial Infarction

Myocardial infarction (MI) remains a major threat to human health due to the limited energy supply, disordered cell metabolism, massive cardiomyocyte death, and restricted regeneration. Although currently available therapies may relieve myocardial damage, restoring the dysregulated energy metabolism to normal levels has not yet been achieved. MOTS-c has recently been identified as a regulator of biological metabolism to combat aging; however, its role in reprogramming cardiac metabolism remains to be elucidated. Here, MOTS-c is chemically conjugated to self-assembling Q11 peptide to fabricate an injectable hydrogel (MQgel) aimed to improve mitochondria function and cardiomyocyte metabolism post-MI. It is observed that MQgel effectively protects mitochondria from oxidative damage and normalized cardiomyocyte metabolism, including glucose uptake, glycolysis, and the tricarboxylic acid (TCA) cycle, thereby inhibiting cardiomyocyte death and enhancing cardiomyocyte activity. In a rat MI model, intramyocardial injection of MQgel successfully minimizes the infarct area and fibrosis, promotes angiogenesis, suppresses myocardial hypertrophy, and improves cardiomyocyte survival and metabolic enzyme activity, all of which collaboratively attenuate the maladaptive cardiac remodeling and boost cardiac function and tissue repair. The findings suggest that the self-assembled mitochondria metabolism-regulatory peptide hydrogel effectively treats MI, and cellular bioenergy modulation provides a new therapeutic approach for tissue repair after injury. The bioenergy peptide hydrogel is successfully fabricated through the supramolecular self-assembling of the MOTS-c-grafted Q11 peptide. The MQgel efficiently restored the metabolism dysfunction and cellular metabolism under oxidative conditions, significantly improved cardiac function, and inhibited cardiac remodeling, offering an alternative therapeutic strategy for cardiovascular disease.image