Copper‐loaded Milk‐Protein Derived Microgel Preserves Cardiac Metabolic Homeostasis After Myocardial Infarction

Abstract Myocardial Infarction (MI) is a leading cause of death worldwide. Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling after MI. However, whether material‐derived cues can treat MI through metabolic regulation is mainly unexplored. Herein, a Cu²⁺ loaded casein microgel (CuCMG) aiming to rescue the pathological intramyocardial metabolism for MI amelioration is developed. Cu²⁺ is an important ion factor involved in metabolic pathways, and intracardiac copper drain is observed after MI. It is thus speculated that intramyocardial supplementation of Cu²⁺ can rescue myocardial metabolism. Casein, a milk‐derived protein, is screened out as Cu²⁺ carrier through molecular‐docking based on Cu²⁺ loading capacity and accessibility. CuCMGs notably attenuate MI‐induced cardiac dysfunction and maladaptive remodeling, accompanied by increased angiogenesis. The results from unbiased transcriptome profiling and oxidative phosphorylation analyses support the hypothesis that CuCMG prominently rescued the metabolic homeostasis of myocardium after MI. These findings enhance the understanding of the design and application of metabolic‐modulating biomaterials for ischemic cardiomyopathy therapy.