Engineered Macrophage Membrane‐Coated S100A9‐siRNA for Ameliorating Myocardial Ischemia‐Reperfusion Injury

Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion‐induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)‐ and RAGE (receptor for advanced glycation end products)‐ comodified macrophage membrane‐coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9‐siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia‐reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane‐coated nanoparticles may represent a new therapeutic intervention for MIRI. This study presents a nanocarrier system that utilizes the assembly of engineered macrophage membranes and cationic polymers to transport siRNA. This nanocarrier system can effectively target the damaged myocardium while avoiding degradation by lysosomes. Genetically modified macrophage membrane‐coated nanoparticles targeting the reduction of S100A8/A9 could serve as a novel therapeutic approach for myocardial ischemia‐reperfusion injury.