Polymers used for the delivery of nucleic acids (NAs) typically possess ionizable, cationic moieties enabling their electrostatic interactions with negatively charged NAs and form stable polyplexes. However, non-cationic building blocks have been harnessed to design cationic polymers with enhanced delivery of DNA/RNA to tissues, cells, and subcellular compartments while remaining stable in biological fluids. By customizing the chemistry of these functional groups, we can improve cell targeting behavior, uptake, endosomal escape, non-toxicity, and transfection efficiency. Additionally, the physicochemical properties, such as the loading capacity, complexation ability, size and morphology, biodegradability, pH sensitivity, and amphiphilicity, can be adjusted based on the specific application. This review summarizes the role of non-cationic moieties in various biomedical contexts, from therapeutic interventions to gene editing. By unpacking and critically summarizing the existing literature, this review provides valuable insights into the rational integration of these building blocks for designing more effective nanovectors to deliver NAs.

中文翻译：

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通过阳离子聚合物设计促进核酸递送：工具箱中的非阳离子构件


用于递送核酸 (NA) 的聚合物通常具有可电离的阳离子部分，使其能够与带负电的 NA 发生静电相互作用并形成稳定的复合物。然而，非阳离子结构单元已被用来设计阳离子聚合物，增强 DNA/RNA 向组织、细胞和亚细胞区室的递送，同时在生物液体中保持稳定。通过定制这些官能团的化学性质，我们可以改善细胞靶向行为、摄取、内体逃逸、无毒性和转染效率。此外，可以根据具体应用调整物理化学性质，例如负载能力、络合能力、尺寸和形态、生物降解性、pH敏感性和两亲性。这篇综述总结了非阳离子部分在各种生物医学领域（从治疗干预到基因编辑）中的作用。通过对现有文献的分析和批判性总结，这篇综述为合理整合这些构建模块以设计更有效的纳米载体来传递 NA 提供了宝贵的见解。