Centro de Ciencias Naturais e Humanas, Universidade Federal do ABC, Santo Andre,Brazil.
Institut Parisien de Chimie Moleculaire, Equipe Chimie des Polymeres, UMR 8232CNRS, Sorbonne University, 4 Place Jussieu, Paris Cedex, 75252,France.
Curr Gene Ther. 2021;21(5):431-451. doi: 10.2174/1566523221666210705130238.
Gene delivery is a promising technology for treating diseases linked to abnormal gene expression. Since nucleic acids are the therapeutic entities in such approach, a transfecting vector is required because the macromolecules are not able to efficiently enter the cells by themselves. Viral vectors have been evidenced to be highly effective in this context; however, they suffer from fundamental drawbacks, such as the ability to stimulate immune responses. The development of synthetic vectors has accordingly emerged as an alternative.
Gene delivery by using non-viral vectors is a multi-step process that poses many challenges, either regarding the extracellular or intracellular media. We explore the delivery pathway and afterwards, we review the main classes of non-viral gene delivery vectors. We further focus on the progresses concerning polyethylenimine-based polymer-nucleic acid polyplexes, which have emerged as one of the most efficient systems for delivering genetic material inside the cells.
The complexity of the whole transfection pathway, along with a lack of fundamental understanding, particularly regarding the intracellular trafficking of nucleic acids complexed to non-viral vectors, probably justifies the current (beginning of 2021) limited number of formulations that have progressed to clinical trials. Truly, successful medical developments still require a lot of basic research.
Advances in macromolecular chemistry and high-resolution imaging techniques will be useful to understand fundamental aspects towards further optimizations and future applications. More investigations concerning the dynamics, thermodynamics and structural parameters of polyplexes would be valuable since they can be connected to the different levels of transfection efficiency hitherto evidenced.
基因传递是一种有前途的治疗与异常基因表达相关疾病的技术。由于核酸是这种方法中的治疗实体，因此需要转染载体，因为大分子本身无法有效地进入细胞。病毒载体在这种情况下已被证明具有很高的有效性；然而，它们存在一些基本的缺陷，例如能够刺激免疫反应。因此，合成载体的开发已经成为一种替代方法。
使用非病毒载体进行基因传递是一个多步骤的过程，无论是在细胞外还是细胞内介质方面都存在许多挑战。我们探索了传递途径，然后回顾了主要类别的非病毒基因传递载体。我们进一步关注聚乙二醇化基于聚合物-核酸聚集体的进展，这些聚集体已成为将遗传物质递送到细胞内部的最有效系统之一。
整个转染途径的复杂性，以及对非病毒载体结合的核酸细胞内运输缺乏基本了解，可能解释了当前（2021 年初）进展到临床试验的制剂数量有限。实际上，成功的医学发展仍然需要大量的基础研究。
大分子化学和高分辨率成像技术的进步将有助于理解进一步优化和未来应用的基本方面。更深入地研究聚集体的动力学、热力学和结构参数将是有价值的，因为它们可以与迄今为止证明的不同转染效率水平联系起来。
