High‐Density Co‐Based Single‐Atom Nanozymes Alleviate Myocardial Ischemia‐Reperfusion Injury by Disrupting the Cycle of Oxidative Stress‐Ferroptosis‐Inflammatory Response

ABSTRACT The vicious cycle of “oxidative stress‐ferroptosis‐inflammatory response” is a key cause of the progression of myocardial ischemia‐reperfusion injury (MIRI), but single antioxidant or anti‐inflammatory therapies have not yielded satisfactory therapeutic effects. In this study, we developed a multi‐functional nanoregulator (HCoMB) based on high‐density Co single‐atom nanozyme (HCoN 4 ) for efficient inhibition of MIRI pathological progression, potentially through disruption of the cycle of “oxidative stress‐ferroptosis‐inflammatory response”. HCoN 4 with 11.05 wt% Co loading exhibited boosted glutathione peroxidase (GPx)‐like activity, superoxide dismutase (SOD)‐like and catalase (CAT)‐like catalytic activities due to the increased metal loading, which not only raised the number of catalytic active centers but also effectively improved the intrinsic activity of individual sites via electron transfer between densely distributed active sites. It can efficiently and stably scavenge ROS, upregulate the expression of glutathione peroxidase 4 (GPx4), and block the core pathway of ferroptosis. In addition, the combination with ML355 could specifically block the p53‐mediated ferroptosis process by inhibiting ALOX12 activity. Mechanistically, the synergistic effect can significantly alleviate lipid peroxidation and oxidative stress injury in cardiomyocytes, and ultimately break the vicious cascade cycle of oxidative stress, ferroptosis and inflammatory response, and realize effective protection against MIRI.