A novel nano-immunoengineering platform combining chimeric antigen receptor (CAR) macrophages and surface-engineered lipid nanoparticles (β-CD LNPs) is developed to enhance efferocytosis and reduce inflammation in atherosclerosis. The CAR macrophages are designed to target and engulf apoptotic cells (ACs) expressing CD47, which are resistant to phagocytosis due to the "don't eat me" signal. The β-CD LNPs, modified with a ROS-responsive moiety, release hydroxypropyl-β-cyclodextrin (HPβ-CD) under oxidative stress, solubilizing cholesterol crystals (CCs) and activating the liver X receptor (LXR) pathway to promote cholesterol efflux and efferocytosis. This dual approach enhances lipid clearance, reduces inflammation, and improves macrophage function. The CAR macrophages also serve as a chimeric switch receptor (CSR), reversing the inhibitory CD47-SIRPα signal to enhance phagocytosis. In vitro and in vivo experiments demonstrate that the CAR-M/β-CD LNP system significantly improves the clearance of CD47hi ACs, reduces CC accumulation, and suppresses inflammatory responses. The platform shows potential for next-generation cardiovascular disease therapies by targeting the root causes of atherosclerosis through enhanced efferocytosis and lipid metabolism. The study highlights the importance of combining CAR engineering with nanoparticle technology to overcome the limitations of traditional therapies and improve outcomes in atherosclerosis.A novel nano-immunoengineering platform combining chimeric antigen receptor (CAR) macrophages and surface-engineered lipid nanoparticles (β-CD LNPs) is developed to enhance efferocytosis and reduce inflammation in atherosclerosis. The CAR macrophages are designed to target and engulf apoptotic cells (ACs) expressing CD47, which are resistant to phagocytosis due to the "don't eat me" signal. The β-CD LNPs, modified with a ROS-responsive moiety, release hydroxypropyl-β-cyclodextrin (HPβ-CD) under oxidative stress, solubilizing cholesterol crystals (CCs) and activating the liver X receptor (LXR) pathway to promote cholesterol efflux and efferocytosis. This dual approach enhances lipid clearance, reduces inflammation, and improves macrophage function. The CAR macrophages also serve as a chimeric switch receptor (CSR), reversing the inhibitory CD47-SIRPα signal to enhance phagocytosis. In vitro and in vivo experiments demonstrate that the CAR-M/β-CD LNP system significantly improves the clearance of CD47hi ACs, reduces CC accumulation, and suppresses inflammatory responses. The platform shows potential for next-generation cardiovascular disease therapies by targeting the root causes of atherosclerosis through enhanced efferocytosis and lipid metabolism. The study highlights the importance of combining CAR engineering with nanoparticle technology to overcome the limitations of traditional therapies and improve outcomes in atherosclerosis.