Autoren:	Settanni, Giovanni Brill, Wolfgang Haas, Heinrich Schmid, Friederike
Titel:	pH-dependent behavior of ionizable cationic lipids in mRNA-carrying lipoplexes investigated by molecular dynamics simulations
Online-Publikationsdatum:	24-Okt-2022
Erscheinungsdatum:	2022
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	Lipid-based nanoparticles and lipoplexes containing ionizable lipids are among the most successful nanocarriers for mRNA-based therapies. The molecular structure of these assemblies is still not fully understood, as well as the role played by the ionizable lipids. SAXS experiments have shown that lipoplexes including the ionizable lipid 2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), under specific conditions, have a lamellar structure, where lipid bilayers are separated by mRNA-rich layers, with an overall spacing between 6.5 and 8.0 nm and a complex pH-dependence. Here, the structure and dynamics of these lipoplexes are investigated at varying pH and mRNA concentration using multiscale molecular dynamics simulations. It is observed that the interaction between DODMA and RNA is slightly attractive only at low pH levels, while it becomes effectively repulsive at high and intermediate pH. This results into a pH-dependent relocation of the RNA inside the multilayers, from the lipid head groups at low pH to a more uniform distribution inside the hydrophilic slabs of the multilayers at high pH. It is also observed that at high pH, DODMA lipids shift toward the hydrophobic part of the bilayer, consequently increasing their leaflet-flipping rate, a phenomenon which may ultimately affect the fusion process of the lipoplex with the endosomal membrane.
DDC-Sachgruppe:	530 Physik 530 Physics
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 08 Physik, Mathematik u. Informatik
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8018
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY-NC-ND
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by-nc-nd/4.0/
Zeitschrift:	Macromolecular rapid communications 43 12
Seitenzahl oder Artikelnummer:	2100683
Verlag:	Wiley-VCH
Verlagsort:	Weinheim
Erscheinungsdatum:	2022
ISSN:	1521-3927
DOI der Originalveröffentlichung:	10.1002/marc.202100683
Enthalten in den Sammlungen:	JGU-Publikationen