索拉非尼是肝癌治疗一线药物，但易引起免疫抑制，调节肿瘤相关巨噬细胞(TAM)由M2型向肿瘤杀伤性M1型极化可逆转肿瘤免疫抑制，增强肝癌治疗效果。本课题基于化疗联合免疫治疗新理念，首次合成纳米凝胶骨架新材料环糊精修饰叠氮化羧甲基壳聚糖(CD-CMCS-N3)和新型酸敏感交联剂炔基修饰的己二酸二酰肼衍生物(yne-H-ADH-H-yne)，利用click反应交联形成多孔智能纳米凝胶，嵌入索拉非尼纳米脂质混悬剂和甘露糖修饰载IKKβ-siRNA纳米粒；纳米凝胶外壳修饰NGR获得逐级靶向智能纳米凝胶。智能纳米凝胶利用NGR靶向肿瘤组织，在肿瘤微环境中pH敏感响应脉冲解聚，释放索拉非尼纳米脂质混悬剂靶向肿瘤细胞发挥化疗作用；释放载IKKβ-siRNA纳米粒靶向M2型TAM，使TAM向M1型极化，逆转肿瘤免疫抑制，发挥免疫化疗协同作用。构建逐级靶向智能载体，为临床开展化疗联合免疫治疗奠定研究基础。

As the first-line drug for hepatic carcinoma treatment, sorafenib showed undesirable tumor-associated immunology effect inhibition which was expected to be reversed by polarizing M2 phenotype of tumor-associated macrophages (TAM) to M1 phenotype in this study. Based on the new treatment concept of chemo-immunotherapy, the aim of this study is to firstly synthesize novel programmable targeting intelligent nanogel to realize co-delivery of sorafenib and IKKβ-siRNA which was found to be efficient in polarizing M2 phenotype to M1 phenotype. A novel skeleton material cyclodextrin modified azided carboxymethyl chitosan (CD-CMCS-N3) and a novel acid sensitive crosslinker adipic acid dihydrazide (yne-H-ADH-H-yne) were synthesized, respectively. The CD-CMCS-N3 would be crosslinked with yne-H-ADH-H-yne based on “click chemistry” mechanism, forming the porous intelligent nanogel. The sorafenib lipid nanosuspension (sorafenib-LNS) and mannose-modified-PEI condensed IKKβ-siRNA nanoparticles (M-PEI/IKKβ-siRNA) would be then embedded to get the co-loaded nanogel. Ad-PEG-NGR would be inserted into CD-CMCS-N3 to get the NGR modified nanogel. The intelligent nanogel will be programmable targeting, of which the initial procedure is to target to tumor site by NGR receptors followed by acid-stimuli impulse degradation. The following procedure contains the hepatoma cells targeting by Sorafenib-LNS and TAM targeting by M-PEI/IKKβ-siRNA, which enhance the M1 phenotype polarization from M2 phenotype and eventually reverse the tumor-associated immunology inhibition. By virtue of the synergistic anti-tumor effects of chemotherapeutics and immunotherapeutic siRNA, this study will make great contributes to the tumor chemo-immunotherapy strategy for clinical applications.