Essential Metal Based Single‐Atom Nanozymes for Myocardial Infarction Therapeutics

Myocardial infarction triggers irreversible cardiomyocyte loss, sustained oxidative stress, and inadequate angiogenesis, often culminating in heart failure. Effective interventions must address these intertwined pathologies with spatiotemporal precision - a goal conventional antioxidants and regenerative strategies fail to achieve. Here, we develop a multifunctional single-atom nanozyme (SAzymes) platform featuring atomically dispersed Fe, Cu, or Mn centers on nitrogen-doped carbon (M-N-C) frameworks. This atomic-level design maximizes catalytic site utilization and broad-spectrum ROS scavenging, while exploiting the intrinsic bioactivity of trace metals. Systematic catalytic profiling identified Fe- Cu-, and Mn-SAzymes as optimal, each exhibiting complementary superoxide dismutase-, catalase-, and peroxidase-like activities. In hypoxia-challenged cardiomyocytes, these SAzymes not only eliminated ROS catalytically but also activated the NRF2/HO-1 endogenous antioxidant pathway, yielding synergistic redox regulation. In a rat MI model, intramyocardial SAzymes delivery preserved ventricular function, reduced infarct size, promoted angiogenesis, attenuated inflammation and fibrosis, and showed no systemic toxicity. Transcriptome analysis further revealed metal-specific therapeutic signatures - with Fe engaging PI3K-Akt/NF-κB, Cu activating AMPK/PPAR, and Mn modulating MAPK/TNF/NF-κB signaling - linking atomic metal identity to distinct biological repair programs. By uniting catalyst engineering with multi-omic mechanistic insight, this study positions trace-metal SAzymes as a versatile and tunable nanomedicine for ischemic heart disease and beyond.