Resolving atheromas and hindering their transition into vulnerable atherosclerotic plaques is imperative to prevent deadly episodes such as heart attacks and strokes. Excess cholesterol accumulation in lesional macrophages switches on a complex inflammatory response in atherosclerosis. Despite the development of new cholesterol-lowering therapies, including of the recently approved PCSK9 small interfering RNA (siRNA) antagonists, patients still face a tremendous risk of developing major acute cardiovascular events resulting from chronic inflammation in the plaque. We previously showed that Epsins, a family of endocytic adaptors, fuel inflammation in atherosclerosis; however, the underlying mechanism and the therapeutic potential of targeting Epsins remains largely unknown. Here, we report that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages, and that inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific nanoparticle (NP) delivery of Epsin siRNAs, we show that silencing of macrophage Epsins markedly diminishes atherosclerotic plaque size and promotes plaque regression. Mechanistically, we demonstrate that Epsins bind to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promote ABCG1 degradation via lysosomes and hamper ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a myeloid-specific Epsin double knockout mouse model (LysM-DKO) with a genetic reduction in ABCG1 (LysM-DKO-ABCG1^fl/+), the enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed. Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits in treating advanced atherosclerosis.