A molecular view on the escape of lipoplexed DNA from the endosome
A molecular view on the escape of lipoplexed DNA from the endosome
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DOI：
10.7554/elife.52012
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发表时间：
2020-04-16
期刊：
影响因子：
7.7
通讯作者：
Marrink, Siewert J.
中科院分区：
文献类型：
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作者：
Bruininks, Bart M. H.;Souza, Paulo C. T.;Marrink, Siewert J.
使用非病毒载体进行体内基因治疗可以大大提高安全性，同时降低制备载体的成本。非病毒载体的一种有前途的方法是利用DNA/阳离子脂质体复合物（lipoplexes）来递送遗传物质。在这里，我们使用粗粒度的分子动力学模拟，探讨有效的DNA转移从lipoplexes的分子机制。我们的脂复合物与内体膜模型的计算融合实验显示了两种不同的转染模式：平行和垂直。在平行融合途径中，DNA与膜表面对齐，在初始融合孔形成后不久显示出遗传物质的非常快速的释放。垂直途径也导致转染，但释放较慢。我们进一步表明，脂质复合物的组成和大小，以及内体膜的脂质组成，在我们的模型中对融合效率有显着的影响。
The use of non-viral vectors for in vivo gene therapy could drastically increase safety, whilst reducing the cost of preparing the vectors. A promising approach to non-viral vectors makes use of DNA/cationic liposome complexes (lipoplexes) to deliver the genetic material. Here we use coarse-grained molecular dynamics simulations to investigate the molecular mechanism underlying efficient DNA transfer from lipoplexes. Our computational fusion experiments of lipoplexes with endosomal membrane models show two distinct modes of transfection: parallel and perpendicular. In the parallel fusion pathway, DNA aligns with the membrane surface, showing very quick release of genetic material shortly after the initial fusion pore is formed. The perpendicular pathway also leads to transfection, but release is slower. We further show that the composition and size of the lipoplex, as well as the lipid composition of the endosomal membrane, have a significant impact on fusion efficiency in our models.