Abstract: Based on the natural affinity between macrophages and atherosclerotic lesions, we made a novel macrophage membrane-coated polylactic acid-glycolic acid copolymer (PLGA) nanoparticle (MPLNPs), and examined its ability targeting atherosclerotic lesions. PLGA nanoparticle (PLGANPs) were prepared by precipitation and MPLNPs were prepared by membrane extrusion. Their morphology, particle size and retainment of functional proteins were characterized. Their targeting capabilities were investigated with cell uptake assay in vitro and fluorescence imaging in vivo. The results showed that MPLNPs were spherical, with obvious core/shell structure, the average particle size was (167 ±6.12) nm, and integrin α4β1 was retained on the surface. Vascular cell adhesion molecule 1 (VCAM-1) receptor was highly expressed in the LPS (lipopolysaccharides)-HUVEC (human umbilical vein endothelial cells) and atherosclerotic lesions in ApoE^-/- mouse model, and the nanoparticles could effectively recognize the VCAM-1 receptor and had good targeting properties in vitro and in vivo. The results suggest that the cell membrane biomimetic nano-carrier may provide a new approach for the targeting strategy in the treatment of atherosclerosis and related diseases.