OBJECTIVE To express recombinant protein PBP-ApoA1 by fusion of P-selectin banding peptide (PBP) and apolipoprotein (ApoA1) by Escherichia coli, and PBP-ApoA1 was applied to further prepare a recombinant high-density lipoprotein (HDL) loading with curcumin (Cur), named PA-rHDL-Cur, for the effective treatment of atherosclerosis (AS) by targeting to activated platelets. METHODS The soluble expression of PBP-ApoA1 was achieved using a co-expression strategy with glutathione S-transferase (GST) tag. The purified PBP-ApoA1, phospholipid and cholesterol were encapsulated with Cur to prepare PA-rHDL-Cur by thin-film hydration method. The physicochemical properties of PA-rHDL-Cur were characterized by particle size analyzer and UV spectrophotometer, while the release stability was evaluated using dialysis method. Cell viability and cellular uptake efficiency of PA-rHDL-Cur were assessed in vitro. Platelet adhesion experiments were conducted to confirm the targeting ability of PA-rHDL towards activated platelets. Furthermore, the antioxidant activity, cholesterol efflux effect, and reduction in oxidized high-density lipoprotein uptake capacity of RAW264.7 macrophages treated with PA-rHDL-Cur were investigated. RESULTS The yield of PBP-ApoA1 obtained by shake flask fermentation and purification was 1.3 g·L^-1. The resulting PA-rHDL-Cur exhibited uniform particle size with an average diameter of (165.3±29.6) nm and the Zeta potential of (-2.19±1.28) mV. The biocompatibility of this drug delivey system was satisfactory. In vitro cell experiments demonstrated that PA-rHDL-Cur effectively targeted atherosclerotic lesions, releasing curcumin to reduce oxidative stress within foam cells at the lesion site, significantly enhancing the bioavailability of Cur. Additionally, the presence of ApoA1 in PA-rHDL facilitated cholesterol efflux, thereby delaying the progression of atherosclerosis. CONCLUSION This design of biomimetic recombinant high-density lipoprotein nano-drug delivery system provides a new approach and theoretical basis for the development of novel nanocarriers against atherosclerosis.