Atherosclerosis (AS) is the leading cause of heart attacks,stroke,and peripheral vascular disease.Berberine (BBR),a botanical medicine,has diversified anti-atherosclerotic effects but with poor absorption.The aim of this study was to develop an effective BBR-entrapped nano-system for treating AS in high-fat diet (HFD)-fed Apoe(/-) mice,and also explore the possible underlying mechanisms involved.Three D-α-tocopherol polyethylene glycol (PEG) succinate (TPGS) analogues with different PEG chain lengths were synthesized to formulate BBR-entrapped micelles.HFD-fed Apoe(-/-) mice were administered with optimized formula (BBR,100 mg/kg/day) orally for 5 months.The artery plaque onset and related metabolic disorders were evaluated,and the underlying mechanisms were studied.Our data showed that,BT1500M increased BBR deposition in liver and adipose by 107.6％ and 172.3％,respectively.In the Apoe(-/-) mice,BT1500M ameliorated HFD-induced hyperlipidemia and lipid accumulation in liver and adipose.BT1500M also suppressed HFD-induced chronic inflammation as evidenced by the reduced liver and adipose levels of interleukin-6 (IL-6),tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β);and decreased plasma level of TNF-α,IL-6,IL-1β,interferon-γ (IFN-γ),monocyte chemotactic protein (MCP),and macrophage inflammatory factor (MIP).The mechanism study showed that BT1500M changed Ampk and Nf-κb gene expression,and interrupted a crosstalk process between adipocytes and macrophages.Further investigation proved that BT1500M decreased endothelial lesion and subsequent macrophage activation,cytokines release,as well as cholesteryl ester gathering in the aortic arch,resulting in ameliorated artery plaque build-up.Our results provide a practical strategy for treating AS using a BBR-entrapped nano-system.