Dual Single‐Atom Engineered NADH Oxidase‐Mimic Boosts In Situ NAD + Biotransformation for Targeted Myocardial Ischemia/Reperfusion Protection

ABSTRACT Myocardial ischemia/reperfusion (I/R) injury is a globally recognized pathological condition that results in life‐threatening organ dysfunction. Supplementation with nicotinamide adenine dinucleotide (NAD + ) can improve myocardial energy metabolism, alleviate inflammation, and mitigate I/R injury. However, its clinical applicability is constrained by the poor efficacy and delivery limitations of current NAD + supplementation strategies. Here, we design a dual single‐atom nanozyme with nicotinamide adenine dinucleotide (NADH) oxidase‐mimicking activity for in situ NAD + biotransformation and I/R injury treatment. Upon M2 macrophage membrane coating, the nanozyme selectively targets ischemic myocardium, facilitating in situ NAD + biotransformation by eliminating excess NADH, while concurrently scavenging reactive oxygen species, restoring mitochondrial bioenergetics, attenuating inflammation, and inhibiting apoptosis. Mechanistic investigations demonstrate that the nanozyme activates the NAD + ‐SIRT1 axis, enhancing ATP biosynthesis and oxidative phosphorylation, while suppressing TNF signaling and NF‐κB pathways. Collectively, the engineered NOX‐like nanozyme offers a novel therapeutic strategy for myocardial I/R injury by modulating both mitochondrial bioenergetics and oxidative stress defense pathways through restoring NAD + /NADH homeostasis.