![]() One, they shield the genetic material from degradation, and two, the lipids support transfection ( Kim et al., 2015 Ciani et al., 2004 Felgner et al., 1987). Lipoplexes consist of (cationic) lipids whose role is twofold. In this work we focus on cationic lipid-DNA based vectors, called lipoplexes. Moreover, lipoplexes are potentially toxic especially if they are highly positively charged ( Huang and Li, 1997). The major downside to many of these non-viral based methods, is that their transfection rates in vivo are rather low ( Tros de Ilarduya et al., 2010 Rezaee et al., 2016 Nayerossadat et al., 2012). Most non-viral vectors use cationic lipids or polymers for complexation with the negatively charged DNA, concealing the genetic material from degradation. Non-viral vectors have two advantages, first, they do not trigger a specific immune response, and second, they are potentially much cheaper than viral vectors. Therefore, ‘new’ non-viral based vectors are being developed. Naked DNA gets quickly degraded in our body by exonucleases, whereas using viruses as vectors can lead to a strong acquired immune response ( Nayak and Herzog, 2010). Most higher organisms have evolved quite stringent measures to block uptake of DNA from their surroundings, preventing excessive genetic instability. Even though the concept of gene therapy has been around for a while, the problem remains to target and enter the right cells, without being toxic to the rest of the organism. The first clinical trials with gene therapy started in the early 90’s, and the first approved therapy being introduced in Europe in 2012 ( Cressey, 2012 Blaese et al., 1995 Hanna et al., 2017). Gene therapy is a promising technique with a wide applicability. 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. The perpendicular pathway also leads to transfection, but release is slower. 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. Our computational fusion experiments of lipoplexes with endosomal membrane models show two distinct modes of transfection: parallel and perpendicular. Here we use coarse-grained molecular dynamics simulations to investigate the molecular mechanism underlying efficient DNA transfer from lipoplexes. A promising approach to non-viral vectors makes use of DNA/cationic liposome complexes (lipoplexes) to deliver the genetic material. The use of non-viral vectors for in vivo gene therapy could drastically increase safety, whilst reducing the cost of preparing the vectors.
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