肝癌微环境中免疫功能紊乱，肿瘤相关巨噬细胞（TAM）是肝癌免疫治疗中的重要靶细胞之一。特异性下调免疫微环境巨噬细胞中的表皮生长因子受体（EGFR）可抑制肝癌生长。传统输送方式脱靶风险高，脱靶下调EGFR可能造成不良反应，甚至促进肝癌生长。本课题已构建程序性响应的BOMB功能纳米载体，拟携带CD68启动子控制的EGFR调控基因，通过肝癌微环境靶向输送及TAM特异性表达，精准干预肝癌微环境中TAM的EGFR功能。研究将以免疫微环境及其中的TAM为对象，评估BOMB体系携带基因药物后的微环境靶向性和TAM特异性；构建肝癌小鼠模型，进行体内TAM靶向性研究和对肝癌免疫微环境重塑作用及机制的研究。本课题借助程序性响应的BOMB载体平台，将改善TAM特异性EGFR调控的精准度及有效性，降低脱靶风险，解决肝癌微环境TAM的靶向调控难题，为免疫治疗临床转化提供有力基础和实践依据。

Immune dysfunction occurs in tumor microenvironment of hepatocellular carcinoma (HCC). Tumor-associated macrophage (TAM) is one of the most important target cells in immune therapy against liver cancer. Macrophage-specific downregulation of epidermal growth factor receptor (EGFR) expression in the immune microenvironment could inhibit HCC growth. Conventional delivery methods may result in a high risk of off-target effect. Off-target EGFR downregulation might cause adverse effect, or may promote liver cancer growth. This study will use an established BOMB delivery system featuring programmed responsiveness, to deliver EGFR regulatory gene controlled by CD68 promoter, which will precisely regulate EGFR expression of TAM in HCC microenvironment via BOMB-mediated targeting ability and TAM specificity. We will also establish HCC mice models to evaluate in vivo TAM targeting function and to investigate the mechanism of immune remodeling in HCC microenvironment. Taking advantage of BOMB system with programmed responsiveness, this study should improve TAM specificity and regulation precision/efficiency to reduce off-target effect, which will eventually solve the problem of TAM targeting. This study will provide strong evidence and practical basis for translational approach in immunotherapy.