本研究旨在开发一种新型双响应性纳米粒子（NP）系统，用于联合传递拓扑异亲核类脱氧核糖核酸（CPT）和编码肿瘤坏死因子相关凋亡诱导配体（pTRAIL） DNA 用于癌症治疗。通过将CPT前药和核酸缩合双（三唑-[12]环N3）基与4-硝基苯甲酸酯通过烷基链连接，得到了三个硝基还原酶（NTR）响应性两亲分子，分别为CNN1-CNN3（分别具有5，8和11个碳链）。其中，CNN2在存在促合脂质DOPE的情况下对HeLa细胞的增殖抑制效果最佳。进一步将由CNN2，pDNA和DOPE组成的NP与ROS响应性硫醚链两性聚合物（TTP）共同组装形成具有平均尺寸为118nm的核壳式NP（CNN2-DT/pDNA），其具有高载药能力、优异的血清耐受性和良好的生物相容性。在ROS、NTR和NADH的存在下，核壳式NP将分解，释放80%的CPT和丰富的pDNA。通过AIE荧光成像清晰观察到了CNN2-DT NP和DNA的自组装和传递过程。体外和体内结果表明，CNN2-DT/pTRAIL NP协同促进了68%的肿瘤细胞凋亡，并抑制了肿瘤生长，副作用可忽略。本研究显示，通过双响应核壳式NP将前药和核酸结合，为癌症治疗提供了一个时间和空间可控的策略。

A novel dual-responsive nanoparticle (NP) system was aimed to be developed for the co-delivery of camptothecin (CPT) and plasmid encoding TNF-related apoptosis-inducing ligand (pTRAIL) DNA in cancer therapy. The combination of the prodrug CPT and the nucleic acid condensing di-(triazole-[12]aneN3) unit with 4-nitrobenzyl ester through alkyl chains resulted in three nitroreductase (NTR) responsive amphiphiles, CNN1-CNN3 (with 5, 8, and 11 carbon chains, respectively). Among them, CNN2 was the most effective in inhibiting the proliferation of HeLa cells in the presence of fusogenic lipid DOPE. The NPs composed of CNN2, pDNA, and DOPE were further co-assembled with ROS-responsive thioketal-linked amphiphilic polymer (TTP) to afford the core-shell NPs (CNN2-DT/pDNA) with an average size of 118 nm, which exhibited high drug-loading capacity, excellent serum tolerance, and good biocompatibility. In the presence of ROS, NTR, and NADH, the core-shell NPs were decomposed, leading to the efficient release of 80% CPT and abundant pDNA. The self-assembly and delivery process of CNN2-DT NPs and DNA were clearly observed through the AIE fluorescent imaging. In vitro and in vivo results demonstrated that the CNN2-DT/pTRAIL NPs synergistically promoted 68% apoptosis of tumor cells and inhibited tumor growth with negligible toxic side effects. This study showed that the combination of prodrug and nucleic acid through dual-responsive core-shell NPs provide a spatially and temporally-controlled strategy for cancer therapy.