Engineered M2 macrophage-derived extracellular vesicles with platelet membrane fusion for targeted therapy of atherosclerosis

Abstract

Atherosclerosis is featured as chronic low-grade inflammation in the arteries, which leads to the formation of plaques rich in lipids. M2 macrophage-derived extracellular vesicles (M₂EV) have significant potential for anti-atherosclerotic therapy. However, their therapeutic effectiveness has been hindered by their limited targeting capability <i>in vivo</i>. The objective of this study was to create the P-M₂EV (platelet membrane-modified M₂EV) using the membrane fusion technique in order to imitate the interaction between platelets and macrophages. P-M₂EV exhibited excellent physicochemical properties, and microRNA (miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers. Remarkably, miR-99a-5p was identified as the miRNA with the highest expression level, which targeted the mRNA of Homeobox A1 (HOXA1) and effectively suppressed the formation of foam cells <i>in vitro.</i> In an atherosclerotic low-density lipoprotein receptor-deficient (<i>Ldlr</i>^<i>-/-</i>) mouse model, the intravenous injection of P-M₂EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles. Crucially, P-M₂EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity. The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.