Current atherosclerosis treatment is based on a combination of cholesterol-lowering medication and low-fat diets; however, the clinical effect is unsatisfactory. It has been shown that the level of immune cell infiltration and pro-inflammatory factors in the atherosclerotic immune microenvironment (AIM) play important roles in the development and progression of atherosclerosis. Therefore, we hypothesized that reshaping "hot AIM" into "cold AIM" could attenuate atherosclerosis. For this purpose, we designed a pH-responsive and charge-reversible nanosystem, referred to as Au-PEI/shSiglec-1/PEI-acetylsalicylic acid (ASPA NPs) to effectively deliver shSiglec-1, which blocked the interactions between macrophages with CD8+ T/NKT cells, thus inhibiting immune cell infiltration. Further, we demonstrated that acetylsalicylic acid (ASA), detached from the pH-responsive PEI-ASA polymer, and inhibited lipid accumulation in macrophage, thereby decreasing the lipid antigen presentation. Additionally, reduced macrophage-produced inflammatory factors by ASA and low CD8+ T/NKT cell infiltration levels synergistically inhibit Th17 cell differentiation, thus further dramatically attenuating inflammation in AIM by decreasing the IL-17A production. Eventually, ASPA NPs efficiently reshaped AIM by inhibiting immune cell infiltration, lipid antigen presentation, and pro-inflammation, which provided a feasible therapeutic strategy for atherosclerosis immunotherapy.

Central European Institute of Technology Brno University of Technology Purkynova 123 CZ 61200 Brno Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno CZ 61300 Brno Czech Republic

School of Pharmaceutical Science Guangdong Provincial Key Laboratory of New Drug Screening Southern Medical University Guangzhou 510515 China

Tianjin Key Laboratory of Drug Delivery and High Efficiency School of Pharmaceutical Science and Technology Tianjin University Tianjin 300072 China

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