改善实体瘤微环境增强肿瘤免疫治疗效应的层状双氢氧化物复合体系的制备及机理研究

改善实体瘤免疫抑制微环境（ITM）已成为肿瘤免疫治疗的一大主流策略。由于ITM的复杂多样性以及免疫药物的低生物利用率，治疗效果往往不尽人意。集多功能于一体的纳米技术为解决这一窘境提供了诸多可能。课题组前期研究发现，层状双氢氧化物复合物（LDH@miR155）能显著促进微环境肿瘤相关巨噬细胞（TAM）向M1型极化，促进T细胞的浸润，扭转ITM抑制状态。本课题拟以可降解介孔硅为核，层状双氢氧化物为壳，筛选出安全可降解的纳米佐剂材料，提高对miRNA的搭载和保护能力，引入肿瘤细胞膜，构建具有肿瘤靶向能力且高效改善ITM的膜-纳米材料-核酸药物纳米仿生复合体系。在小鼠荷瘤模型中通过检测TAM表型、效应细胞和抑制细胞浸润数量及功能变化，相关细胞因子的分泌水平变化综合研究复合体系改善ITM的作用效果，揭示其作用机理，评估其与免疫检查点抑制剂α-PD-1联合治疗的协同效应，为肿瘤免疫治疗提供新思路。

The improvement of immunosuppressive tumor microenvironment (ITM) has become a mainstream strategy in cancer immunotherapy. Due to the complex diversity of ITM and low bioavailability of immune drugs, the therapeutic effect is often unsatisfactory. Multi-functional nanotechnology offers many potentials to solve this dilemma. In the previous study of our group, we found that layered double hydroxides complex (LDH@miR155) can significantly promote the polarization of tumor-associated macrophages (TAM) to M1-type and increase the proportion of T lymphocytes in the microenvironment and thus reverse the depressed state of ITM. This subject intends to use degradable mesoporous silica as the core and layered double hydroxides as the shell to select safe and degradable nano-adjuvant materials, which can enhance the ability to carry and protect miRNA and improve ITM efficiently combined with tumor cell membrane for tumor targeting, so as to build a membrane-nanomaterial-nucleic acid drug nano-bionic composite system. In tumor-burdened mice model, we synthetically evaluate the ability of composite system to improve ITM by detecting the TAM phenotypes, infiltration ratio and functional changes of immune effector cells and immunosuppressive cells and secretion levels of the relevant chemokines. Finally, we will investigate the mechanism of the composite system improving ITM and assess the therapeutic effect of the composite system combined with α-PD-1. Our subject will provide new ideas for cancer immunotherapy.