Atherosclerosis is an important pathological basis for cardiovascular disease. Thus, the treatment of atherosclerosis can effectively improve the prognosis and reduce the mortality of cardiovascular diseases. In this study, we developed simvastatin acid (SA)-loaded cross-linked dendrimer nanoparticles (SA PAM) that were adsorbed to the surface of red blood cells (RBCs) to obtain SA PAM@RBCs, a ROS and shear stress dual response drug delivery system for the treatment of atherosclerosis. SA PAM could continuously release SA in an H2O2-triggered manner, and effectively eliminate excessive H2O2 in LPS-stimulated RAW 264.7 cells, achieving the target of using the special microenvironment at the plaque to release drugs. At the same time, the shear sensitive model also proved that only 12.4% of SA PAM detached from the RBCs under low shear stress (20 dynes per cm2), while 61.3% SA PAM desorbed from the RBCs under a high shear stress (100 dynes per cm2) stimulus, revealing that SA PAM could desorb in response to the shear stress stimulus. Both the FeCl3 model and ApoE-/- model showed that SA PAM@RBCs had better therapeutic effects than free SA, and with excellent safety in vivo. Therefore, a biomimetic drug delivery system with dual sensitivity to ROS and shear stress would become a promising strategy for the treatment of atherosclerosis.