Cationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF12.5%, TKPF25% and TKPF50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Such gene vectors exhibited the following features: (1) fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions; (2) The fluorophilic effect mediated efficient cellular uptake and endosomal escape; (3) ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. Notably, TKPFs also exhibited great serum resistance in gene delivery and TKPF50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrates that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application.

中文翻译：

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ROS 响应性聚乙烯亚胺基氟化聚合物可提高转染效率并降低细胞毒性。

阳离子聚合物聚乙烯亚胺 (PEI) 在基因传递中起着至关重要的作用。然而，高分子量 PEI 导致更高的转染效率和更高的细胞毒性，而低分子量 PEI 表现出较低的转染性能和较低的毒性。因此，需要对 PEI 进行有效的化学修饰以增强转染活性和提高生物相容性。在这里，通过将低分子量 PEI (PEI 1.8K) 与硫缩酮 (TK) 接头，然后在其表面修饰七氟丁酸酐。这样的基因载体表现出以下特点：(1)氟化降低了正电荷密度并赋予疏水和疏油特性以抵抗血清相互作用；(2) 亲氟效应介导有效的细胞摄取和内体逃逸；(3) ROS 响应的 TK 接头允许多聚体分解以降低聚阳离子的细胞毒性并改善有效载荷在特定位点的释放。TKPFs 在体外的多个细胞系（293TN 细胞和 B16F10 细胞）中获得了优异的转染效率，并表现出优异的生物相容性。值得注意的是，TKPFs 在基因传递中也表现出很大的血清抗性，并且在 70% FBS 存在下，TKPF50% 转染了近 80% 的细胞。