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Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes

[Image: see text] Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and lat...

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Autores principales: Spadea, Alice, Jackman, Mark, Cui, Lili, Pereira, Sara, Lawrence, M. Jayne, Campbell, Richard A., Ashford, Marianne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264317/
https://www.ncbi.nlm.nih.gov/pubmed/35758331
http://dx.doi.org/10.1021/acsami.2c06065
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author Spadea, Alice
Jackman, Mark
Cui, Lili
Pereira, Sara
Lawrence, M. Jayne
Campbell, Richard A.
Ashford, Marianne
author_facet Spadea, Alice
Jackman, Mark
Cui, Lili
Pereira, Sara
Lawrence, M. Jayne
Campbell, Richard A.
Ashford, Marianne
author_sort Spadea, Alice
collection PubMed
description [Image: see text] Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and late endosomal membranes are studied, for the first time, using different reflectometry techniques. Novel insight is provided with respect to the subphase pH, the stage of the endosome, and the nature of the nucleic acid cargo. It is found that the insertion of lipids from the LNPs into the model membrane is greatest at pH 6.5 and 5.5, whereas at higher pH, lipid insertion is suppressed with evidence instead for the binding of intact LNPs, demonstrating the importance of the pH in the fusion of LNPs undergoing the endosomal pathway. Furthermore, and independently of the pH, the effect of the early- versus late-stage endosomal models is minimal, suggesting that the increased fluidity and anionic nature of the late endosome has little effect on the extent of LNP interaction. Last, there is greater nucleic acid delivery from LNPs containing mRNA than Poly(A), indicating that the extent of interaction can be tuned according to the nature of the nucleic acid cargo. Such new information on the relative impact of factors influencing nucleic acid delivery by LNP interactions with endosomal membranes is important in the design and tuning of vehicles with improved nucleic acid delivery capacities.
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spelling pubmed-92643172022-07-09 Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes Spadea, Alice Jackman, Mark Cui, Lili Pereira, Sara Lawrence, M. Jayne Campbell, Richard A. Ashford, Marianne ACS Appl Mater Interfaces [Image: see text] Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and late endosomal membranes are studied, for the first time, using different reflectometry techniques. Novel insight is provided with respect to the subphase pH, the stage of the endosome, and the nature of the nucleic acid cargo. It is found that the insertion of lipids from the LNPs into the model membrane is greatest at pH 6.5 and 5.5, whereas at higher pH, lipid insertion is suppressed with evidence instead for the binding of intact LNPs, demonstrating the importance of the pH in the fusion of LNPs undergoing the endosomal pathway. Furthermore, and independently of the pH, the effect of the early- versus late-stage endosomal models is minimal, suggesting that the increased fluidity and anionic nature of the late endosome has little effect on the extent of LNP interaction. Last, there is greater nucleic acid delivery from LNPs containing mRNA than Poly(A), indicating that the extent of interaction can be tuned according to the nature of the nucleic acid cargo. Such new information on the relative impact of factors influencing nucleic acid delivery by LNP interactions with endosomal membranes is important in the design and tuning of vehicles with improved nucleic acid delivery capacities. American Chemical Society 2022-06-27 2022-07-06 /pmc/articles/PMC9264317/ /pubmed/35758331 http://dx.doi.org/10.1021/acsami.2c06065 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Spadea, Alice
Jackman, Mark
Cui, Lili
Pereira, Sara
Lawrence, M. Jayne
Campbell, Richard A.
Ashford, Marianne
Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title_full Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title_fullStr Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title_full_unstemmed Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title_short Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes
title_sort nucleic acid-loaded lipid nanoparticle interactions with model endosomal membranes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264317/
https://www.ncbi.nlm.nih.gov/pubmed/35758331
http://dx.doi.org/10.1021/acsami.2c06065
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