Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina

Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modifie...

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Autores principales: Gautam, Milan, Jozic, Antony, Su, Grace Li-Na, Herrera-Barrera, Marco, Curtis, Allison, Arrizabalaga, Sebastian, Tschetter, Wayne, Ryals, Renee C., Sahay, Gaurav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575971/
https://www.ncbi.nlm.nih.gov/pubmed/37833442
http://dx.doi.org/10.1038/s41467-023-42189-3
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author Gautam, Milan
Jozic, Antony
Su, Grace Li-Na
Herrera-Barrera, Marco
Curtis, Allison
Arrizabalaga, Sebastian
Tschetter, Wayne
Ryals, Renee C.
Sahay, Gaurav
author_facet Gautam, Milan
Jozic, Antony
Su, Grace Li-Na
Herrera-Barrera, Marco
Curtis, Allison
Arrizabalaga, Sebastian
Tschetter, Wayne
Ryals, Renee C.
Sahay, Gaurav
author_sort Gautam, Milan
collection PubMed
description Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modified PEG-lipids, and neutral unmodified PEG-lipids (LNP). Subretinal injections of LNPa containing Cre mRNA in the mouse show tdTomato signal in the retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx and LNPz show 27% and 16% photoreceptor transfection, respectively, with striking localization extending from the photoreceptor synaptic pedicle to the outer segments, displaying pan-retinal distribution in the photoreceptors and RPE. LNPx containing Cas9 mRNA and sgAi9 leads to the formation of an oval elongated structure with a neutral charge resulting in 16.4% editing restricted to RPE. Surface modifications of LNPs with PEG variants can alter cellular tropism of mRNA. LNPs enable genome editing in the retina and in the future can be used to correct genetic mutations that lead to blindness.
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spelling pubmed-105759712023-10-15 Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina Gautam, Milan Jozic, Antony Su, Grace Li-Na Herrera-Barrera, Marco Curtis, Allison Arrizabalaga, Sebastian Tschetter, Wayne Ryals, Renee C. Sahay, Gaurav Nat Commun Article Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modified PEG-lipids, and neutral unmodified PEG-lipids (LNP). Subretinal injections of LNPa containing Cre mRNA in the mouse show tdTomato signal in the retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx and LNPz show 27% and 16% photoreceptor transfection, respectively, with striking localization extending from the photoreceptor synaptic pedicle to the outer segments, displaying pan-retinal distribution in the photoreceptors and RPE. LNPx containing Cas9 mRNA and sgAi9 leads to the formation of an oval elongated structure with a neutral charge resulting in 16.4% editing restricted to RPE. Surface modifications of LNPs with PEG variants can alter cellular tropism of mRNA. LNPs enable genome editing in the retina and in the future can be used to correct genetic mutations that lead to blindness. Nature Publishing Group UK 2023-10-13 /pmc/articles/PMC10575971/ /pubmed/37833442 http://dx.doi.org/10.1038/s41467-023-42189-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gautam, Milan
Jozic, Antony
Su, Grace Li-Na
Herrera-Barrera, Marco
Curtis, Allison
Arrizabalaga, Sebastian
Tschetter, Wayne
Ryals, Renee C.
Sahay, Gaurav
Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title_full Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title_fullStr Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title_full_unstemmed Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title_short Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
title_sort lipid nanoparticles with peg-variant surface modifications mediate genome editing in the mouse retina
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575971/
https://www.ncbi.nlm.nih.gov/pubmed/37833442
http://dx.doi.org/10.1038/s41467-023-42189-3
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