Synergistic enhancement of efferocytosis and cholesterol efflux via macrophage biomimetic nanoparticle to attenuate atherosclerosis progression

Atherosclerosis is the leading cause of myocardial infarction and stroke, which is characterized as a chronic inflammatory disease due to the aberrant accumulation of apoptotic cells in the necrotic core. Previous CD47-SIRPα checkpoint blockage strategies based on monoclonal antibodies or nanoparticles have shown significant pro-efferocytosis effects and thus improved the inflammatory microenvironment of plaque. However, apoptotic foam cells and concentrated cholesterol render plaque macrophages an overwhelming lipid burden, limiting the pro-efferocytosis effect of checkpoint blockade therapy in atherosclerosis. In this study, we fabricate a retinoic acid-loaded macrophage membrane-biomimetic liposome (R@MLP) to improve the efferocytosis ability of macrophages further. Mechanistically, the innate existence of SIRPα on the R@MLP would block the binding of CD47 on apoptotic cells with SIRPα on macrophages to realize the CD47-SIRPα inhibition. Consequently, engulfing retinoic acid in R@MLP would upregulate the expression of ABCA1 and ABCG1 of macrophages and enhance cholesterol efflux. In the mouse model of atherosclerosis, which benefited from the macrophage membrane, R@MLP showed ideal inflammation targeting ability to plaques and further reinforced the efferocytosis ability of macrophages. Ultimately, R@MLP shifted macrophages to the anti-inflammatory state and attenuated the progression of atherosclerosis. R@MLP synergizes checkpoint inhibition and cholesterol efflux to boost pro-efferocytosis therapy and presents a novel anti-inflammatory therapeutic strategy for atherosclerosis management.