为了提高纳米载体的肿瘤渗透性能，揭示其多级结构与细胞之间相互作用的机理，本课题通过多重点击等化学手段构筑一系列具有可控膜穿透和定位壳脱落功能的阳离子半胱氨酸共聚物。利用季铵化和硫醚烷基化调控聚合物的质子缓冲能力、疏水性质和高级结构，使用计算机模拟和实验表征其多级自组装行为，通过细胞实验研究纳米载体在细胞摄取和内体逃逸过程中发挥膜穿透作用的关键因素。在此基础上，使用酸敏感性不同的聚乙二醇胺实现阳离子载体在肿瘤细胞外和细胞内定位脱壳的能力，并探索其在病灶区域不同位置壳脱落行为对细胞内在化的协同作用机理。进一步以抗癌药物或RNA为模型，证明纳米给药系统在体外和动物体内对耐药肿瘤的可控穿透性能和治疗效果，阐明聚合物载体化学结构和多级组装结构与体内外肿瘤穿透性之间的基本科学问题，为高效细胞内药物传递系统的设计提供理论指导和新思路，并为恶性肿瘤，特别是耐药肿瘤的临床化疗提供一种具有应用潜力的纳米载体。

To improve the tumor penetration of nanocarriers and reveal the mechanism of interaction between the hierarchical structures of nanovehicles and tumor cells, a class of cationic L-cysteine-based copolymers with controlled membrane activity and on-demand shell-detachment ability were constructed via multiple click reactions. The proton buffering capacity, hydrophobic characteristics, and secondary and tertiary structures of copolymers were controlled by the quaterisation and thioether alkylation of side chains. The hierarchical self-assembly of copolymers were characterized using both computational and experimental techniques. Thereafter, cell experiments were carried out to demonstrate the key role in the penetrability of nanoassemblies during cellular uptake and endosomal escape. Furthermore, a series of poly(ethylene glycol) amines with different pH-sensitivity were designed and synthesized, for the further preparation of a novel cationic nanocarrier capable of shedding its outer corona under extracellular and intracellular environments. The synergistic effect of shell-detachment at various locations on the cell internalization of nanoparticles was investigated. In addition, the nanovehicles were loaded with antitumor drugs or RNA as model therapeutics to verify the controllable penetrability and therapeutic effects of nanoformulations against drug resistant tumors in vitro and in vivo, and to systematically address the fundamental scientific issues between the chemical and assembled structures of polymeric nanocarriers and their tumor penetrating capacity. This work provides guidance and a new strategy for the design of effective intracellular drug delivery systems, and offers a promising nanovehicle for the clinical treatment of cancer, particularly drug-resistant tumors.