Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery.

IRD gene delivery lipid nanoparticle mRNA retinal degeneration

Journal

Small (Weinheim an der Bergstrasse, Germany)
ISSN: 1613-6829
Titre abrégé: Small
Pays: Germany
ID NLM: 101235338

Informations de publication

Date de publication:
13 May 2024
Historique:
revised: 20 04 2024
received: 01 02 2024
medline: 13 5 2024
pubmed: 13 5 2024
entrez: 13 5 2024
Statut: aheadofprint

Résumé

Complete encapsulation of nucleic acids by lipid-based nanoparticles (LNPs) is often thought to be one of the main prerequisites for successful nucleic acid delivery, as the lipid environment protects mRNA from degradation by external nucleases and assists in initiating delivery processes. However, delivery of mRNA via a preformed vesicle approach (PFV-LNPs) defies this precondition. Unlike traditional LNPs, PFV-LNPs are formed via a solvent-free mixing process, leading to a superficial mRNA localization. While demonstrating low encapsulation efficiency in the RiboGreen assay, PFV-LNPs improved delivery of mRNA to the retina by up to 50% compared to the LNP analogs across several benchmark formulations, suggesting the utility of this approach regardless of the lipid composition. Successful mRNA and gene editors' delivery is observed in the retinal pigment epithelium and photoreceptors and validated in mice, non-human primates, and human retinal organoids. Deploying PFV-LNPs in gene editing experiments result in a similar extent of gene editing compared to analogous LNP (up to 3% on genomic level) in the Ai9 reporter mouse model; but, remarkably, retinal tolerability is significantly improved for PFV-LNP treatment. The study findings indicate that the LNP formulation process can greatly influence mRNA transfection and gene editing outcomes, improving LNP treatment safety without sacrificing efficacy.

Identifiants

pubmed: 38738752
doi: 10.1002/smll.202400815
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2400815

Subventions

Organisme : ODCDC CDC HHS
ID : P51 OD011092
Pays : United States
Organisme : NEI NIH HHS
ID : 1R01EY033423-01A1 (G.S.)
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY010572
Pays : United States
Organisme : NIH HHS
Pays : United States

Informations de copyright

© 2024 Wiley‐VCH GmbH.

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Auteurs

Yulia Eygeris (Y)

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, 97201, USA.

Michael I Henderson (MI)

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, 97201, USA.

Allison G Curtis (AG)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.

Antony Jozić (A)

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, 97201, USA.

Jonathan Stoddard (J)

Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.

Rene Reynaga (R)

Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.

Kathleen R Chirco (KR)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.

Grace Li-Na Su (GL)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.

Martha Neuringer (M)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.

Andreas K Lauer (AK)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.

Renee C Ryals (RC)

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.

Gaurav Sahay (G)

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, 97201, USA.
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97201, USA.
Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97201, USA.

Classifications MeSH