Shear Stress and ROS Dual-Responsive RBC-Hitchhiking Nanoparticles for Atherosclerosis Therapy

Atherosclerosis (AS), a leading cause of death worldwide, is a chronic inflammatory disease rich in lipids and reactive oxygen species (ROS) within plaques. Therefore, lowering lipid and ROS levels is effective in treating AS and reducing AS-induced mortality. In this study, an intelligent biomimetic drug delivery system that specifically responded to both shear stress and ROS microenvironment was developed, consisting of red blood cells (RBCs) and cross-linked polyethyleneimine nanoparticles (SA PEI) loaded with a lipid-lowering drug simvastatin acid (SA), and RBCs were self-assembled with SA PEI to obtain biresponsive SA PEI@RBCs for the treatment of AS. SA PEI could achieve sustained release of SA in response to ROS and reduce ROS and lipid levels to achieve the purpose of treating AS. Shear stress model experiments showed that SA PEI@RBCs could respond to the high shear stress level (100 dynes/cm 2 ) at plaques, realizing the desorption and enrichment of SA PEI and improving the therapeutic efficiency of SA PEI@RBCs. In vitro and in vivo experiments have confirmed that SA PEI@RBCs exhibits better in vivo safety and therapeutic efficacy than SA PEI and free SA. Therefore, shaping SA PEI@RBCs into a biomimetic drug delivery system with dual sensitivity to ROS and shear stress is an effective strategy and treatment to facilitate their delivery into plaques.