Enhanced FGF21 Delivery via Neutrophil-Membrane-Coated Nanoparticles Improves Therapeutic Efficacy for Myocardial Ischemia–Reperfusion Injury

Acute myocardial infarction, a leading cause of death globally, is often associated with cardiometabolic disorders such as atherosclerosis and metabolic syndrome. Metabolic treatment of these disorders can improve cardiac outcomes, as exemplified by the GLP-1 agonist semaglutide. Fibroblast growth factor 21 (FGF21), a novel metabolic regulator, plays pivotal roles in lipid mobilization and energy conversion, reducing lipotoxicity, inflammation, mitochondrial health, and subsequent tissue damage in organs such as the liver, pancreas, and heart. Here, we test the therapeutic efficacy of FGF21 in mice with ischemia-reperfusion (I/R) injury, a model of acute myocardial infarction. We employed the strategic method of coating the FGF21-encapsulating liposomal nanoparticles with a neutrophil membrane designed to camouflage FGF21 from macrophage-mediated efferocytotic clearance and promote its targeted accumulation at I/R foci due to the inherent neutrophilic attraction to the inflammatory site. Our findings revealed that the coated FGF21 nanoparticles markedly accumulated within the lesions with a prolonged half-life, in additional to the liver, leading to substantial improvements in cardiac performance by enhancing mitochondrial energetic function and reducing oxidative stress, inflammation, and cell death. Therefore, our research highlights a viable strategy for the enhanced delivery of therapeutical FGF21 analogs to lesions beyond the liver following myocardial infarction.