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Effective interventions must address these intertwined pathologies with spatiotemporal precision \u2014 a goal conventional antioxidants and regenerative strategies fail to achieve. Here, we develop a multifunctional single\u2010atom nanozyme (SAzymes) platform featuring atomically dispersed Fe, Cu, or Mn centers on nitrogen\u2010doped carbon (M\u2013N\u2013C) frameworks. This atomic\u2010level design maximizes catalytic site utilization and broad\u2010spectrum ROS scavenging, while exploiting the intrinsic bioactivity of trace metals. Systematic catalytic profiling identified Fe\u2010 Cu\u2010, and Mn\u2010SAzymes as optimal, each exhibiting complementary superoxide dismutase\u2010, catalase\u2010, and peroxidase\u2010like activities. In hypoxia\u2010challenged cardiomyocytes, these SAzymes not only eliminated ROS catalytically but also activated the NRF2\/HO\u20101 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\u2010specific therapeutic signatures \u2014 with Fe engaging PI3K\u2013Akt\/NF\u2010\u03baB, Cu activating AMPK\/PPAR, and Mn modulating MAPK\/TNF\/NF\u2010\u03baB signaling \u2014 linking atomic metal identity to distinct biological repair programs. By uniting catalyst engineering with multi\u2010omic mechanistic insight, this study positions trace\u2010metal SAzymes as a versatile and tunable nanomedicine for ischemic heart disease and beyond.<\/jats:p>","DOI":"10.1002\/adhm.202505365","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:53:02Z","timestamp":1770641582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Essential Metal Based Single\u2010Atom Nanozymes for Myocardial Infarction Therapeutics"],"prefix":"10.1002","volume":"15","author":[{"given":"Ziliang","family":"Fu","sequence":"first","affiliation":[{"name":"Ciechanover Institute of Precision and Regenerative Medicine School of Medicine The Chinese University of Hong Kong Shenzhen  Shenzhen Guangdong P. R. China"},{"name":"Joint Laboratory of CUHKSZ\u2010Dalian Practical Biotechnology The Chinese University of Hong Kong  Shenzhen Guangdong P. R. 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