Synergistic enhancement of efferocytosis and cholesterol efflux via macrophage biomimetic nanoparticle to attenuate atherosclerosis progression
Shiteng Cai, Jinfeng Gao, Xueyi Weng, Zhengmin Wang, Danwen Zheng, Qiaozi Wang, Qiyu Li, Chengzhi Han, Weiyan Li, Jing Chen, Yuyuan Fu, Yiwen Tan, Bo Wei, Zhiqing Pang, Zheyong Huang, Yanan Song, Junbo Ge
Abstract
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. • Retinoic acid-loaded macrophage membrane-biomimetic liposome R@MLP blocks CD47-SIRPα. • Retinoic acid upregulates ABCA1/ABCG1, boosting macrophage cholesterol efflux. • Biomimetic liposome targets plaques, boosting efferocytosis and M2 polarization. • Retinoic acid-loaded macrophage membrane-biomimetic liposome slows atherosclerosis.