Toward understanding lipid reorganization in RNA lipid nanoparticles in acidic environments.

Autor:	Garaizar A; Drug Discovery Sciences, Bayer Pharmaceuticals, Wuppertal 42113, Germany.; Computational Life Science, Bayer Crop Science, Monheim am Rhein 40789, Germany., Díaz-Oviedo D; Drug Discovery Sciences, Bayer Pharmaceuticals, Wuppertal 42113, Germany., Zablowsky N; Lead Discovery, Nuvisan Innovation Campus Berlin, Berlin 13353, Germany., Rissanen S; Chemical and Pharmaceutical Development, Bayer Pharmaceuticals, Turku 20210, Finland., Köbberling J; Drug Discovery Sciences, Bayer Pharmaceuticals, Wuppertal 42113, Germany., Sun J; Chemical and Pharmaceutical Development, Bayer Pharmaceuticals, Berlin 13353, Germany., Steiger C; Chemical and Pharmaceutical Development, Bayer Pharmaceuticals, Berlin 13353, Germany., Steigemann P; Lead Discovery, Nuvisan Innovation Campus Berlin, Berlin 13353, Germany., Mann FA; Chemical and Pharmaceutical Development, Bayer Pharmaceuticals, Berlin 13353, Germany., Meier K; Drug Discovery Sciences, Bayer Pharmaceuticals, Wuppertal 42113, Germany.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 05; Vol. 121 (45), pp. e2404555121. Date of Electronic Publication: 2024 Oct 30.
DOI:	10.1073/pnas.2404555121
Abstrakt:	The use of lipid nanoparticles (LNPs) for therapeutic RNA delivery has gained significant interest, particularly highlighted by recent milestones such as the approval of Onpattro and two mRNA-based SARS-CoV-2 vaccines. However, despite substantial advancements in this field, our understanding of the structure and internal organization of RNA-LNPs -and their relationship to efficacy, both in vitro and in vivo- remains limited. In this study, we present a coarse-grained molecular dynamics (MD) approach that allows for the simulations of full-size LNPs. By analyzing MD-derived structural characteristics in conjunction with cellular experiments, we investigate the effect of critical parameters, such as pH and composition, on LNP structure and potency. Additionally, we examine the mobility and chemical environment within LNPs at a molecular level. Our findings highlight the significant impact that LNP composition and internal molecular mobility can have on key stages of LNP-based intracellular RNA delivery. Competing Interests: Competing interests statement:All authors are current employees of Bayer AG or Nuvisan ICB GmbH.
Databáze:	MEDLINE
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