免疫逃逸在肿瘤侵袭与转移中扮演重要角色，是导致肿瘤复发和难以治愈的重要原因。研究表明，肿瘤细胞和微环境间质细胞分泌的大量免疫抑制因子，是诱发免疫耐受的关键因素。通过 RNA干扰下调这些因子的表达，可以重塑肿瘤微环境，恢复肿瘤免疫特征。Toll样受体9（TLR9）过表达于多种肿瘤相关免疫细胞的内涵体膜，其膜内结构域与胞嘧啶-鸟嘌呤（CpG）特异性亲合，可启动固有免疫响应且有助于CpG偶联载体逃逸内涵体。本组曾构筑系列可激活细胞穿透肽（ACPP）修饰的载体，实现了小干扰RNA（siRNA）靶向到肿瘤组织、细胞甚至细胞器。在此基础上，我们拟结合酸敏感ACPP、还原敏感键（二硫键）和内涵体膜内受体介导机制，构建一种新型的多支链修饰脂质载体，靶向递送CpG和siRNA到TLR9+肿瘤免疫细胞群，分别定位于理想场所（内涵体和细胞浆），发挥免疫抑制调节和响应增强的双重作用，达到更理想的肿瘤免疫治疗效果。

As the major determinant of tumor recurrence and growth, tumor immune escape plays a key role in the process of tumor invasion and metastasis. Studies have shown that the immune tolerance can be attributed to the abundant immunosuppressive cytokine originated from tumor cell and tumor stromal cell, and the corresponding downregulation by RNA interference, can lead to the remodeling of the tumor microenvironment, which is characterized by the recovery of tumor immune activity. Toll-like receptor 9(TLR9) is overexpressed in a variety of tumor-associated cells and localized on endosome membrane. The specific affinity between TLR9's intra-endosomal domain and cytosine-guanine(CpG) sequence, can initiate the innate immune response and facilitate the endosome escape of the CpG-linked cargoes. Our group has ever built series of nano-sized delivery systems with the modification of activatable cell-penetrating peptides(ACPPs), offering small interfering RNA(siRNA) the favorable delivery to tumor tissues, cells and even organelles. Based on our previous studies, we aim to develop a multifunctional arm-modified lipid carrier, which combine ACPPs, redox-sensitive linker (disulfide bonds) and the intra-endosomal receptor-mediated domain. Utilizing this system, both CpG and siRNA can suffer from selective delivery to TLR9+ tumor immune cells population as well as their ideal subcellular organelles (endosome and cytoplasma) , which regulate the immune inhibition, enhance immune response, and achieve a more efficient tumor immunotherapy ultimately.