Conventionally, polycations are pharmacological inert used as nonviral gene delivery vectors with the sole function of compacting and protecting nucleic acids. Here, the first autophagy-inhibiting cationic polymer delivering plasmid DNA (pDNA) encoding TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is prepared for cancer gene therapy. The copolymerization of methacryloyl chloroquine (MACQ) with 2-(dimethylamino)ethyl methacrylate (DMAEMA) not only improves transfection efficacy through hydrophobic modification, but also endows the copolymer with autophagy-blocking capability, which further sensitizes cancer cells to TRAIL induced apoptosis. Importantly, the designed copolymer shows efficient TRAIL expression, autophagy inhibition and enhances TRAIL-induced apoptosis in an autophagy-dependent manner. In contrast, TRAIL gene delivered by the autophagy-blocking-deficient control copolymer without the chlorine atom presents weaker antitumor efficacy, although expressing a similar amount of therapeutic TRAIL protein. Thus, this study demonstrates a conceptually new approach in which the therapeutic outcome of the delivered gene can be inherently strengthened by the delivery vehicle with intrinsic pharmacological activity.

常规地，聚阳离子是用作非病毒基因递送载体的药理学惰性，其唯一具有压缩和保护核酸的功能。在此，制备了第一个自噬抑制性阳离子聚合物，该聚合物传递了编码TRAIL（肿瘤坏死因子相关的凋亡诱导配体）的质粒DNA（pDNA），用于癌症基因治疗。甲基丙烯酰氯喹（MACQ）与甲基丙烯酸2-（二甲氨基）乙酯（DMAEMA）的共聚不仅可以通过疏水修饰提高转染效率，而且还赋予该共聚物自噬功能，进一步使癌细胞对TRAIL诱导的细胞凋亡敏感。重要的是，设计的共聚物显示出有效的TRAIL表达，自噬抑制作用并以自噬依赖性方式增强TRAIL诱导的凋亡。相反，尽管表达了相似量的治疗性TRAIL蛋白，但无氯原子的自噬封闭缺陷对照共聚物所递送的TRAIL基因显示出较弱的抗肿瘤功效。因此，该研究证明了一种概念上新的方法，其中可以通过具有内在药理活性的递送载体来内在地增强所递送基因的治疗结果。