A molecular view on the escape of lipoplexed DNA from the endosome

Abstract
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Abstract

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.

Data availability

All raw data of fusion experiments and analysis software amount to TBs of data, so are available upon request. A data package has been prepared and deposited to Dryad, under the DOI 10.5061/dryad.fqz612jq4

The following data sets were generated

(2020) A molecular view on the escape of lipoplexed DNA from the endosome (no trajectories)
Dryad Digital Repository, doi:10.5061/dryad.fqz612jq4.

https://doi.org/10.5061/dryad.fqz612jq4

Article and author information

Author details

Bart Marlon Herwig Bruininks

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5136-0864
Paulo C T Souza

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

Competing interests
No competing interests declared.
Helgi Ingolfsson

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

Competing interests
No competing interests declared.
Siewert-Jan J Marrink

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

For correspondence
s.j.marrink@rug.nl

Competing interests
Siewert-Jan J Marrink, S.J.M acknowledges funding from the ERC through an Advanced grant COMP-MICR-CROW-MEM".".

"This ORCID iD identifies the author of this article:" 0000-0001-8423-5277

Funding

H2020 European Research Council (COMP-MICR-CROW-MEM)

Siewert-Jan J Marrink

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.