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

Milan Gautam, Antony Jozic, Grace Li-Na Su, Marco Herrera-Barrera, Allison Curtis, Sebastian Arrizabalaga, Wayne Tschetter, Renee C. Ryals () and Gaurav Sahay ()
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Milan Gautam: Oregon State University
Antony Jozic: Oregon State University
Grace Li-Na Su: Oregon Health & Science University
Marco Herrera-Barrera: Oregon State University
Allison Curtis: Oregon Health & Science University
Sebastian Arrizabalaga: Oregon Health & Science University
Wayne Tschetter: Oregon Health & Science University
Renee C. Ryals: Oregon Health & Science University
Gaurav Sahay: Oregon State University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42189-3

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