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J Control Release. 2015 Nov 10;217:345-51. doi: 10.1016/j.jconrel.2015.08.007. Epub 2015 Aug 8.

Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes.

Author information

1
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Acuitas Therapeutics, Vancouver, V6T 1Z3 BC, Canada.
3
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dreww@mail.med.upenn.edu.

Abstract

In recent years, in vitro transcribed messenger RNA (mRNA) has emerged as a potential therapeutic platform. To fulfill its promise, effective delivery of mRNA to specific cell types and tissues needs to be achieved. Lipid nanoparticles (LNPs) are efficient carriers for short-interfering RNAs and have entered clinical trials. However, little is known about the potential of LNPs to deliver mRNA. Here, we generated mRNA-LNPs by incorporating HPLC purified, 1-methylpseudouridine-containing mRNA comprising codon-optimized firefly luciferase into stable LNPs. Mice were injected with 0.005-0.250mg/kg doses of mRNA-LNPs by 6 different routes and high levels of protein translation could be measured using in vivo imaging. Subcutaneous, intramuscular and intradermal injection of the LNP-encapsulated mRNA translated locally at the site of injection for up to 10days. For several days, high levels of protein production could be achieved in the lung from the intratracheal administration of mRNA. Intravenous and intraperitoneal and to a lesser extent intramuscular and intratracheal deliveries led to trafficking of mRNA-LNPs systemically resulting in active translation of the mRNA in the liver for 1-4 days. Our results demonstrate that LNPs are appropriate carriers for mRNA in vivo and have the potential to become valuable tools for delivering mRNA encoding therapeutic proteins.

KEYWORDS:

Luciferase; Nanoparticle; Non-viral gene delivery; Pseudouridine; mRNA

PMID:
26264835
PMCID:
PMC4624045
DOI:
10.1016/j.jconrel.2015.08.007
[Indexed for MEDLINE]
Free PMC Article

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