Biomimetic Macrophage Membrane and Lipidated Peptide Hybrid Nanovesicles for Atherosclerosis Therapy

Abstract Atherosclerosis is the underlying cause for cardiovascular disease. Current pharmacotherapies are limited by the inadequate targeting and insufficient treatment. Herein, inspired by the interaction of macrophage and lipoprotein as a typical hallmark of atherosclerosis, hybrid nanovesicles (MLP‐NVs) are designed by fusion of anti‐inflammatory M2‐phenotype macrophage membranes and lipidated peptide (DOPE‐pp‐HBSP) to mimic the binding manner of cell‐lipoprotein for atherosclerotic treatment. Through hybridization of M2 macrophage membranes and lipidated peptide film, MLP‐NVs facilitate the inflammatory cell internalization at atherosclerotic site, and sequester the proinflammatory cytokines to suppress local inflammation. Moreover, MLP‐NVs exhibit a matrix metalloprotease 2 (MMP2)‐responsive release of the peptide HBSP in plaques, leading to the restoration of dysfunctional endothelial cells. In the ApoE^−/− mice with atherosclerosis, simvastatin‐loaded MLP‐NVs provide comprehensive treatment by inherent inflammation suppression, endothelial repair, and cholesterol efflux capacities, resulting in atherosclerotic plaques regression. Through closely mimicking physiological cues, this biomimetic hybrid nanovesicle platform provides a potential strategy for anti‐atherosclerotic therapy.