AS微环境调控巨噬细胞-纳米框架联合递送载体的构建及其机制研究

粥样动脉硬化（AS）由于病灶斑块组织血流快、多发性、结构复杂的病理特征是AS递药的最大障碍。巨噬细胞参与AS病程的发生、发展全过程，具有免疫调控性。本项目针对AS病理特点，分别构建ROS/pH双重敏感的H2S供体（OA-SCS-JK1）和anti-miR155聚精氨酸阳离子纳米粒，并将二者通过MMP-2敏感纳米框架装载（RJK1miR-SNCs），再采用M1型巨噬细胞膜包裹后构建得到一种能够主动靶向血管内斑块，且具斑块微环境响应、粒径可控的纳米递释载体（RJK1miR SNCs@M1）。经细胞膜包裹后的纳米框架在特异性趋动下到达斑块组织，利用载体表面可吸附炎性因子、H2S供体对巨噬细胞的极化作用、载基因纳米粒入胞调控等多重作用下，抑制AS炎性反应发生及斑块形成。本项目从组织、细胞、分子层面全面重塑AS病灶组织微环境，创新性强，有望真正解决AS治疗瓶颈。

The pathological feathers of atherosclerosis (AS) including high blood flow, multiple sclerosis, and complicated pathological structure have composed the biggest challenge for drug delivery to the site of disease. Macrophages play a vital role in the progress of atherosclerosis in the way of immunoregulating. The aim of this study will focus on the design of ROS/pH dual-responsive H2S donor (OA-SCS-JK1) and anti-miR155 poly(arginine) nanoparticle (miR NPs) and incorporated them into metalloproteinase-2(MMP-2) responsive nano-framework. Subsequently, M1 macrophage membrane was isolated and fused on the surface of the nano-framework to construct plaque microenvironment responsive nanoparticle named as RJK1miR SNCs@M1, which are expected to display active targeting to plaques and have controllable size range. RJK1miR SNCs@M1 could target to plaques due to the presence of macrophage membrane on the surface and its ability of absorbing board-spectrum pro-inflammatory factors. Meanwhile, OA-SCS-JK1 could release H2S to polarize M2 macrophage, and miR NPs could regulate the function of foam cells to inhibit the development of plaques. By remodeling AS microenvironment at histological, cellular and molecule level with our innovative nano-scaled drug delivery systems, it will be promising to break the barriers for better atherosclerosis management.