Snowflake‐Like RuMn Branched Nanosheets Enable Topocatalytic Therapy of Cardiac Ischemia/Reperfusion Injury via Resisting Inflammatory Cascade and Neutrophil Invasion

Abstract Myocardial ischemia/reperfusion (I/R) injury is the main cause for limited response to treatment after clinical revascularization. The primary mechanisms are over production of reactive oxygen and nitrogen species (RONS) and severe inflammatory response, leading to irreversible damage to cardiac tissue. Herein, this work proposes the concept of topocatalytic nanomedicine and reports a distinctive class of snowflake‐like ultrathin manganese‐doped ruthenium branched nanosheets with PEGylation (RuMn BNSP) that could overcome complex biological conditions to attenuate myocardial I/R injury. The snowflake‐like RuMn BNSP mimic the function of antioxidative enzymes to effectively scavenge RONS, thereby enabling the excellent cellular protection against oxidative stress. In addition, in an oxidized environment, the snowflake‐like RuMn BNSP could maintain mitochondrial function by preventing mitochondrial membrane potential depolarization and mitochondrial permeability transition pore opening. In a myocardial I/R murine model, a single intravenous bolus of RuMn BNSP prevents the recruitment of inflammatory neutrophils and amplification of inflammatory responses in cardiac tissue, thereby reducing the size of myocardial infarction and improving the cardiac function. These findings validate the rational design of snowflake‐like RuMn BNSP to effectively scavenge toxic RONS and reduce neutrophil infiltration on myocardial I/R injury, providing strong evidence for the application of RuMn BNSP in other oxidative stress‐related diseases.