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

By N. Pardi, Steven Tuyishime, Hiromi Muramatsu, K. Karikó, B. Mui, Ying K. Tam, T. D. Madden, M. Hope, D. Weissman. Journal of Controlled Release, 2015

893 citations recorded by the source corpus.

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 0.005–0.250 mg/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 10 days. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4b85f626ae0fbac2271094864455e2e7ad3db12d

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Citations in the corpus

Concurrent human antibody andTH1 type T-cell responses elicited by a COVID-19 RNA vaccine (2020, background): “It is molecularly well defined, free of animal-origin materials and synthesized by an efficient, cell-free in vitro transcription process from DNA templates 4,8,9 .”
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. (2019, positive): “Average protein production half-life from transfected modified mRNA ranges from 50 h in vitro to 7–30 h in vivo, depending on the administration route.(99) The Anderson group(100) has recently shown that synthetically designed exogenous circular RNAs provide up to a 3-fold increase in the half-life ”
mRNA Vaccines in the COVID-19 Pandemic and Beyond. (2021, methodology): “Ionizable LNPs were originally designed to deliver siRNA to the liver but were repurposed to deliver mRNA starting in 2015 and were found to be extremely efficient carriers (70) and potent inducers of adaptive immunity (52).”
mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability (2021, positive): “Another successful and currently widely used approach is to encapsulate and protect the mRNA in LNPs (Pardi et al., 2015).”