Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA
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Published version
Author(s)
Blakney, Anna K
McKay, Paul F
Yus, Bárbara Ibarzo
Aldon, Yoann
Shattock, Robin J
Type
Journal Article
Abstract
Self-amplifying RNA (saRNA) is a promising biotherapeutic tool that has been used as a vaccine against both infectious diseases and cancer. saRNA has been shown to induce protein expression for up to 60 days and elicit immune responses with lower dosing than messenger RNA (mRNA). Because saRNA is a large (~9500 nt), negatively charged molecule, it requires a delivery vehicle for efficient cellular uptake and degradation protection. Lipid nanoparticles (LNPs) have been widely used for RNA formulations, where the prevailing paradigm is to encapsulate RNA within the particle, including the first FDA-approved small-interfering siRNA therapy. Here, we compared LNP formulations with cationic and ionizable lipids with saRNA either on the interior or exterior of the particle. We show that LNPs formulated with cationic lipids protect saRNA from RNAse degradation, even when it is adsorbed to the surface. Furthermore, cationic LNPs deliver saRNA equivalently to particles formulated with saRNA encapsulated in an ionizable lipid particle, both in vitro and in vivo. Finally, we show that cationic and ionizable LNP formulations induce equivalent antibodies against HIV-1 Env gp140 as a model antigen. These studies establish formulating saRNA on the surface of cationic LNPs as an alternative to the paradigm of encapsulating RNA.
Date Issued
2019-07-12
Date Acceptance
2019-06-28
Citation
Gene Therapy, 2019, 26, pp.363-372
ISSN
0969-7128
Publisher
Springer Nature [academic journals on nature.com]
Start Page
363
End Page
372
Journal / Book Title
Gene Therapy
Volume
26
Copyright Statement
© The Author(s) 2019. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, aslong as you give appropriate credit to the original author(s) and thesource, provide a link to the Creative Commons license, and indicate ifchanges were made. The images or other third party material in thisarticle are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is notincluded in the article’s Creative Commons license and your intendeduse is not permitted by statutory regulation or exceeds the permitteduse, you will need to obtain permission directly from the copyrightholder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/
Sponsor
Engineering & Physical Science Research Council (EPSRC)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31300730
PII: 10.1038/s41434-019-0095-2
Grant Number
EP/R013764/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
MESSENGER-RNA VACCINES
INFLUENZA-A VIRUS
PROTECTIVE EFFICACY
NONVIRAL DELIVERY
IMMUNE-RESPONSES
DENDRITIC CELLS
INDUCTION
ENVELOPE
VITRO
Biotechnology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2019-07-12