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-...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-SIRPαcheckpoint 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 SIRPαon the R@MLP would block the binding of CD47 on apoptotic cells with SIRPαon macrophages to realize the CD47-SIRPαinhibition.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 effer-ocytosis 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.展开更多
基金the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0537800)the National Natural Science Foundation of China(82470263,824B2008)the Shanghai Rising-Star Program(24YF2704600).
文摘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-SIRPαcheckpoint 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 SIRPαon the R@MLP would block the binding of CD47 on apoptotic cells with SIRPαon macrophages to realize the CD47-SIRPαinhibition.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 effer-ocytosis 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.
