Bioadaptive spatiotemporal nanomedicine promotes metabolic recovery after myocardial infarction through NAD⁺ and UCP2 regulation

Myocardial infarction causes persistent mitochondrial and metabolic dysfunction that drives adverse cardiac remodeling. Here we develop NAD⁺-genipin nanomedicine for metabolic balance (NGB), a physiologically adaptive nanomedicine with staged intracellular release. In a mouse myocardial infarction model, NGB preferentially accumulates in ischemic myocardium, rapidly replenishes nicotinamide adenine dinucleotide (NAD⁺) and subsequently provides mitochondria-associated sustained NAD⁺-genipin exposure. This phase-linked delivery limits early mitochondrial stress, apoptosis and inflammation and later restores coordination between oxidative phosphorylation, glycolysis and fatty-acid utilization. Mechanistically, NGB supports sirtuin-1-associated oxidative metabolism and suppresses sustained upregulation of the mitochondrial uncoupling protein 2 (UCP2). In hypoxic cardiomyocytes, UCP2 knockdown plus NAD⁺ supplementation partially reproduces the NGB metabolic phenotype, whereas UCP2 overexpression and sirtuin 1 inhibition reverse distinct components of NGB-mediated respiratory and glycolytic recovery. NGB thereby reduces fibrosis and ventricular remodeling and preserves cardiac function, supporting temporally coordinated metabolic intervention after myocardial infarction.