Asymmetric nanozymes improve cardiac purine catabolism and alleviate oxidative stress of myocardium to treat ischemic heart disease

Ischemic heart disease (IHD) refers to a condition with myocardial ischemia, hypoxia, and even cardiomyocyte death due to coronary artery stenosis or occlusion. Energy metabolism gets disturbed by imbalanced ATP synthesis and degradation, while conversion of hypoxanthine to xanthine degraded from ATP synchronously provokes excessive reactive oxygen species (ROS). Metabolic disturbance and oxidative stress are pivotal features of IHD, both of which are associated with increased purine catabolizing enzyme activity of xanthine oxidoreductase (XOR). Here, we construct mushroom-like asymmetric nanozyme (CeAu MAN) through symmetry-breaking synthesis of ceria and gold nanoparticles, which function with XOR-inhibitory effects in cardiac purine metabolism. Mechanistically, superior superoxide dismutase (SOD)-like and catalase (CAT)-like activities of CeAu MAN reduce intracellular ROS levels and diminish oxidative stress-induced cardiomyocyte apoptosis. As revealed by metabolomics in conjunction with purine-related metabolites, CeAu MANs constrain purine degradation pathways by inhibiting metabolic conversion of xanthine into uric acid in the injured myocardium through a heterointerface-mediated affinity to XOR. We also demonstrated therapeutic efficacy of CeAu MANs in MI/RI mice including improved heart function, attenuated maladaptive remodeling, and reliable biocompatibility in three weeks. Symmetry-breaking mushroom-like CeAu MANs improve cardiac purine catabolism and spark an innovative paradigm in metabolic therapy of IHD.