肠道巨噬细胞NF-κB信号通路的活化，在溃疡性结肠炎（UC）发病中起关键作用，抑制其活化成为治疗UC的有效靶点。本项目通过构建靶向结肠炎症部位巨噬细胞的口服给药系统递送siRNA和药物，抑制NF-κB信号通路活化，阻断炎症级联反应。首先制备甘露糖修饰共载siRNA和布地奈德的纳米粒（NP），并包载于氧化敏感的炎症靶向水凝胶纤维（GEL-NP）中，再以HPMCAS包衣制备pH敏感微球。在结肠环境中，该pH敏感微球溶解释放GEL-NP，其借静电作用黏附于炎症部位，在炎症过氧化环境中其所含二硒键断裂并释放NP；NP通过表面甘露糖主动靶向巨噬细胞，并借助聚乙烯亚胺的溶酶体逃逸作用，完成NF-κBp65 siRNA和布地奈德的传递，实现RNA干扰与药物发挥协同作用。在考察给药系统制备工艺和各级生物响应性的基础上，通过动物实验评价其有效性。本项目可为靶向炎症部位巨噬细胞治疗UC提供新的研究思路和方法。

The activation of NF-κB signaling pathway in colonic macrophages plays a key role in the pathogenesis of ulcerative colitis, therefore, the inhibition of NF-κB could become an effective target for ulcerative colitis treatment. In this study, we aimed to develop an oral colon-specific drug delivery system for targeting and co-delivering drugs and siRNA to macrophages at the inflammatory site, in order to inhibit the activation of NF-κB signaling pathway and block the inflammatory cascade. Briefly, a mannose-modified nanoparticle (NP) that co-delivery NF-κBp65 siRNA and budesonide is developed and loaded in a redox-sensitive hydrogel microfiber (GEL-NP), which is further coated with hydroxypropyl methylcellulose acetate succinate to form a pH-sensitive microsphere (MP-GEL-NP). In the colon environment, the MP-GEL-NP is degraded at alkaline pH and releases the GEL-NP, which could adhere to the inflammatory site by electrostatic adsorption, meanwhile, the diselenide bonds contained in the GEL-NP would be specifically cleaved in the inflammatory environment for further releasing the NP. Subsequently, the NP could actively target the macrophages via mannose receptor-mediated endocytosis. Finally, the polyethyleneimine unit contained in the NP would achieve the intracellular release of NF-κBp65 siRNA and budesonide through the ability of endosomal escape. Consequently, the RNA interference and the glucocorticoid might provide a synergistic effect on the treatment of ulcerative colitis. Finally, based on the investigation of the preparation process and the multi bio-responsiveness of the system, the therapeutic effect of MP-GEL-NP is evaluated by animal experiments. This study could also provide new research idea and methods for the treatment of ulcerative colitis through targeting the macrophages at the inflammatory site.