Combination of Backbone Rigidity and Richness in Aryl Structures Enables Direct Membrane Translocation of Polymer Scaffolds for Efficient Gene Delivery,Biomacromolecules

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Combination of Backbone Rigidity and Richness in Aryl Structures Enables Direct Membrane Translocation of Polymer Scaffolds for Efficient Gene Delivery
Biomacromolecules ( IF 5.5 ) Pub Date : 2023-11-09 , DOI: 10.1021/acs.biomac.3c00682
Ying Liu ₁ , Leyue Zhou _{1,

2} , Xiang Xu ₃ , Zehong Cheng ₁ , Yajie Chen ₁ , Xue-Ao Mei ₁ , Nan Zheng ₃ , Chunhui Zhang ₄ , Yugang Bai ₁

Affiliation

The development of cell-penetrating polymers with endocytosis-independent cell uptake pathways has emerged as a prominent strategy to enhance the transfection efficiency. Inspired by the rigid α-helical structure that endows polypeptides with cell-penetrating ability, we propose that a rigid backbone can facilitate the corresponding polymer vector’s performance in gene delivery by bypassing the difficult endosomal escape process. Meanwhile, the installation of aromatic domains, as a way to promote gene transfection efficiency, is employed through the construction of a poly(benzyl ether) (PBE)-based scaffold in this work. We demonstrate that the direct membrane translocation capability of the synthesized PBE contributes to its enhanced transfection performance and excellent biocompatibility profile, rendering the imidazolium-functionalized PBE scaffold with higher activity and biocompatibility. Molecular details of the PBE–lipid interaction are also revealed in molecular dynamics simulations, indicating the important roles of individual structural elements on the polymeric scaffold in the membrane penetration process.

中文翻译：

主链刚性和芳基结构丰富性的结合使聚合物支架能够直接进行膜易位，从而实现高效的基因传递

开发具有不依赖内吞作用的细胞摄取途径的细胞穿透聚合物已成为提高转染效率的重要策略。受赋予多肽细胞穿透能力的刚性α螺旋结构的启发，我们提出刚性主链可以通过绕过困难的内体逃逸过程来促进相应的聚合物载体在基因递送中的性能。同时，在这项工作中，通过构建基于聚（苄基醚）（PBE）的支架来安装芳香结构域，作为提高基因转染效率的一种方式。我们证明，合成的 PBE 的直接膜转位能力有助于其增强的转染性能和优异的生物相容性，使咪唑功能化的 PBE 支架具有更高的活性和生物相容性。分子动力学模拟中还揭示了 PBE-脂质相互作用的分子细节，表明聚合物支架上的各个结构元素在膜渗透过程中的重要作用。

更新日期：2023-11-09

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