A molecular view on the escape of lipoplexed DNA from the endosome (no trajectories)

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.