Engineered neutrophil membrane nanosystem for targeted siRNA therapy in myocardial ischemia-reperfusion injury.

Despite the widespread use of emergency coronary reperfusion therapy, effectively managing reperfusion-induced myocardial injury remains a major clinical challenge. Neutrophil infiltration and the release of damage-associated molecular patterns (DAMPs), particularly the alarmin S100A8/A9, play pivotal roles in driving post-ischemic inflammation and exacerbating myocardial damage. To address this, we developed engineered neutrophil membrane-coated nanoparticles (ENM/RNA NPs) co-loaded with S100A9-targeting siRNA and G0-C14 to alleviate ischemia/reperfusion-induced cardiomyocyte injury. These biomimetic NPs leverage lymphocyte function-associated antigen-1 (LFA-1) overexpression on engineered neutrophil membranes to achieve inflammation-responsive myocardial targeting, thereby competitively blocking intercellular adhesion molecule-1 (ICAM-1)-mediated neutrophil-endothelial interactions and subsequent infiltration. Moreover, hemagglutinin (HA) expressed on the surface of ENM/RNA NPs facilitates endosomal escape, preserving siRNA integrity and function. In a murine model of myocardial ischemia/reperfusion injury (MI/RI), intravenously administered ENM/RNA NPs selectively accumulated in ischemic myocardium and significantly downregulated S100A9 expression in both serum and cardiac tissues. This intervention effectively attenuated neutrophil recruitment, reduced infarct size, and improved cardiac function. Collectively, our findings demonstrate a biomimetic siRNA delivery system based on neutrophil membrane engineering that modulates the S100A8/A9 axis, offering a promising targeted therapeutic strategy for MI/RI.