Zhou Yue, Wang Siyu, Liang Xiaoyang, Heger Zbynek, Xu Min, Lu Qiang, Yu Meng, Adam Vojtech, Li Nan
Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-61300 Brno, Czech Republic.
ACS Nano. 2022 Jul 26;16(7):10517-10533. doi: 10.1021/acsnano.2c01778. Epub 2022 Jun 28.
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.
目前的动脉粥样硬化治疗方法是将降胆固醇药物与低脂饮食相结合；然而，临床效果并不理想。研究表明，动脉粥样硬化免疫微环境（AIM）中的免疫细胞浸润水平和促炎因子在动脉粥样硬化的发生和发展中起着重要作用。因此，我们假设将“热AIM”重塑为“冷AIM”可以减轻动脉粥样硬化。为此，我们设计了一种pH响应性和电荷可逆的纳米系统，称为Au-PEI/shSiglec-1/PEI-乙酰水杨酸（ASPA NPs），以有效递送shSiglec-1，其阻断巨噬细胞与CD8 T/NKT细胞之间的相互作用，从而抑制免疫细胞浸润。此外，我们证明，从pH响应性PEI-ASA聚合物上脱离的乙酰水杨酸（ASA）抑制巨噬细胞中的脂质积累，从而减少脂质抗原呈递。此外，ASA降低巨噬细胞产生的炎症因子以及低水平的CD8 T/NKT细胞浸润协同抑制Th17细胞分化，从而通过降低IL-17A的产生进一步显著减轻AIM中的炎症。最终，ASPA NPs通过抑制免疫细胞浸润、脂质抗原呈递和促炎作用有效地重塑了AIM，为动脉粥样硬化免疫治疗提供了一种可行的治疗策略。
