Abstract 468: Nano-targeting Epsin In Cholesterol Uptake-efflux Fortifies Atheroma Regression

Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In our study, we determined the role of Epsins in macrophage-mediated metabolic regulation and developed a method to target macrophage Epsins with specially-designed S2P-conjugated lipid nanoparticles (NPs), which encapsulate siRNAs to suppress Epsins.We used scRNA-seq with our newly developed algorithm MEBOCOST to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. The NPs targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis.We revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing macrophage-specific NP delivery of Epsin siRNAs, we showed that silencing of macrophage Epsins markedly diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport.Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis.