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Polyplexes Are Endocytosed by and Trafficked within Filopodia.
Biomacromolecules ( IF 6.2 ) Pub Date : 2020-03-02 , DOI: 10.1021/acs.biomac.9b01610
Nilesh P Ingle 1 , Joseph K Hexum 1 , Theresa M Reineke 1
Affiliation  

The improvement of nonviral gene therapies relies to a large extent on understanding many fundamental physical and biological properties of these systems. This includes interactions of synthetic delivery systems with the cell and mechanisms of trafficking delivery vehicles, which remain poorly understood on both the extra- and intracellular levels. In this study, the mechanisms of cellular internalization and trafficking of polymer-based nanoparticle complexes consisting of polycations and nucleic acids, termed polyplexes, have been observed in detail at the cellular level. For the first time evidence has been obtained that filopodia, actin projections that radiate out from the surface of cells, serve as a route for the direct endocytosis of polyplexes. Confocal microscopy images demonstrated that filopodia on HeLa cells detect external polyplexes and extend into the extracellular milieu to internalize these particles. Polyplexes are observed to be internalized into membrane-bound vesicles (i.e., clathrin-coated pits and caveolae) directly within filopodial projections and are subsequently transported along actin to the main cell body for potential delivery of the nucleic acids to the nucleus. The kinetics and speed of polyplex trafficking have also been measured. The polyplex-loaded vesicles were also discovered to traffic between two cells within filopodial bridges. These findings provide novel insight into the early events of cellular contact with polyplexes through filopodial-based interactions in addition to endocytic vesicle trafficking-an important fundamental discovery to enable advancement of nonviral gene editing, nucleic acid therapies, and biomedical materials.

中文翻译:

多聚体被丝状伪足吞噬并在其中被运输。

非病毒基因疗法的改进在很大程度上取决于对这些系统许多基本物理和生物学特性的了解。这包括合成传递系统与细胞的相互作用以及运输传递媒介的机制,这在细胞外和细胞内水平上仍知之甚少。在这项研究中,已经在细胞水平上详细观察了由聚阳离子和核酸组成的基于聚合物的纳米粒子复合物的细胞内化和运输机制,称为聚复合物。首次获得证据表明,丝状伪足是从细胞表面放射出来的肌动蛋白投射物,是多聚体直接内吞的一种途径。共聚焦显微镜图像表明,HeLa细胞上的丝状伪足可检测到外部多链体,并延伸到细胞外环境中以内化这些颗粒。观察到多链体直接在丝虫的突起内被内化成膜结合的囊泡(即网格蛋白包被的凹坑和小窝),随后沿肌动蛋白转运至主要细胞体,以潜在地将核酸递送至核。聚合物运输的动力学和速度也已被测量。还发现载有多聚体的囊泡在丝状桥中的两个细胞之间运输。
更新日期:2020-04-23
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