Asymmetrically Coordinated Cu Single-Atom Nanozyme to Accelerate Inflammation and Immune Homeostasis Modulation in Acute Myocardial Infarction

Single-atom nanozymes (SANs), characterized by tunable electronic properties and optimized atomic utilization efficiency, have attracted considerable attention for biomedical applications. Despite significant progress, their catalytic performance remains inferior to that of natural enzymes, largely attributable to symmetric coordination and an electronic structure. Herein, we successfully engineer a bromine (Br) doping copper (Cu)-based SAN with asymmetric coordination (Cu-BrN3/SAN@M), which exhibits higher catalytic performances compared to its symmetric counterpart, Cu-N4/SAN@M. The high electronegativity of Br causes a slight elongation of the Cu–N bonds in Cu-BrN3/SAN@M, optimizing the adsorption and desorption of oxygen intermediates, thereby markedly enhancing catalytic activity. Density functional theory (DFT) calculations state that asymmetric coordination in the Cu-BrN3/SAN@M configuration strengthens the activation of structural electrons and shifts the d-band center of Cu atoms closer to the Fermi level. This facilitates the adsorption and activation of hydrogen peroxide, hydroxyl radicals, and superoxide anions, confirming their enhanced capability for reactive oxygen species elimination. Experimental results indicate that Cu-BrN3/SAN@M preserves cardiomyocyte viability and functional connectivity by scavenging excess reactive oxygen species (ROS) , reprogramming proinflammatory M1 macrophages toward the reparative M2 phenotype, and amplifying regulatory T cell activity. Collectively, these effects enable robust modulation of the inflammatory microenvironment and restoration of immune homeostasis in an acute myocardial infarction model.