Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes
Open accessAbstract
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.
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BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.
“BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.”
From Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine (2020) · cites this paper as [5]
The Materials and methods sections 2.3–2.4 describe nucleoside-modified mRNA encapsulated in lipid nanoparticles, supporting the general formulation described. But the mRNA studied encoded firefly luciferase; the paper does not identify BNT162b2 or describe a prefusion-stabilized, membrane-anchored SARS-CoV-2 spike protein. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs.
“LNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs (5–9).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [5]
The Results (§3.2; page unavailable) report mRNA-LNP-driven protein production in mouse liver, lung, and muscle, supporting delivery to multiple tissues and organs. The paper does not establish that the mRNA-LNP complexes have “excellent biocompatibility”; its Introduction describes safety evidence for similarly composed LNPs used to deliver siRNA, not the mRNA-LNP complexes studied here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmRNA vaccines have many different but convenient routes for vaccine administration, including subcutaneous, intramuscular, intradermal, intratracheal, intravenous and intraperitoneal routes.
“This highlights one advantage of mRNA vaccines because it has many different but convenient routes for vaccine administration, including subcutaneous, intramuscular, intradermal, intratracheal, intravenous and intraperitoneal routes [31].”
From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [31]
The Discussion lists all six routes used to deliver nucleoside-modified mRNA-LNPs, and the Abstract reports protein expression after administration to mice. The study tested luciferase expression, not vaccine administration or whether these routes are convenient for vaccination. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe expression pattern was similar to results from other LNP formulations.
“which was similar to the results from other LNP formulations (Bahl et al., 2017; Pardi et al., 2015).”
From A thermostable mRNA vaccine against COVID-19 (2020) · cites this paper as Pardi et al., 2015
Pardi et al. found that after intravenous injection of luciferase mRNA LNPs, the highest measured luminescence was at 0.2 days.
“For instance, Pardi et al. found that after intravenous injection of luciferase mRNA LNPs, the highest measured luminescence was at 0.2 days.47”
From Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing (2024) · cites this paper as [47]
The spike protein is a class I fusion protein that binds ACE2 on host cells and triggers virus-cell membrane fusion.
“The S protein is a class I fusion protein that facilitates binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface, which triggers fusion between the virus and cell membrane110,148,149.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [110]
More robust germinal centre responses are consistent with antigen dissemination to multiple lymph nodes and the self-adjuvating characteristics of the mRNA-lipid nanoparticle vaccine platform compared to nonadjuvanted inactivated vaccines used for seasonal influenza virus vaccination.
“More robust germinal centre responses are consistent with antigen dissemination to multiple lymph nodes and the self-adjuvating characteristics of the mRNA–lipid nanoparticle vaccine platform compared to nonadjuvanted inactivated vaccines used for seasonal influenza virus vaccination7,20,21.”
From SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses (2021) · cites this paper as [20]
One of the greatest challenges in developing mRNA vaccines is their poor stability.
“However, one of the greatest challenges encountered when developing mRNA vaccines is their poor stability.”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Pardi et al., 2015
Encapsulating mRNA in LNPs reduces premature mRNA degradation after administration.
“Another successful and currently widely used approach is to encapsulate and protect the mRNA in LNPs (Pardi et al., 2015). This reduces premature mRNA degradation after administration”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Pardi et al., 2015
Naked mRNA is quickly degraded after administration.
“Early research on mRNA vaccines has demonstrated that naked mRNA is quickly degraded after administration (Pardi et al., 2015, Wayment-Steele et al., 2020).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Pardi et al., 2015
Transfection of human dendritic cells with mRNA LNPs in vitro was reported to be promoted in the presence of ApoE.
“the transfection of human DCs with mRNA LNPs in an in vitro setting was also reported to be promoted in the presence of ApoE [42]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [42]
Administration routes can greatly influence organ distribution, expression kinetics and therapeutic outcomes of lipid nanoparticle-mRNA formulations.
“Administration routes can greatly influence organ distribution, expression kinetics and therapeutic outcomes of lipid nanoparticle–mRNA formulations143,144.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [143]
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Nucleoside modified mRNA vaccines for infectious diseases
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Self-citationRecent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases
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Self-citationChemically modified hCFTR mRNAs recuperate lung function in a mouse model of cystic fibrosis
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MethodSelf-citationIonizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease
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Self-citationSelf-Amplifying RNA Approach for Protein Replacement Therapy
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Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
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Self-citation
- Authors
- Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- Acuitas Therapeutics (Canada) (CA)
- Corresponding author
- Weissman, Drew
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 217
- Pages
- 345-351
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC4624045
- OpenAlex
- W1420726270
- Cited by
- 1,014
- References
- 27
- Citations by year
- 2026: 125 · 2025: 137 · 2024: 145 · 2023: 161 · 2022: 142 · 2021: 145 · 2020: 53 · 2019: 32 · 2018: 37 · 2017: 26 · 2016: 8 · 2015: 3
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Controlled Release (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bill and Melinda Gates Foundation CAVD (R01-AI-050484, R01-AI-090788)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA delivery, lipid nanoparticles, nucleoside-modified mRNA, firefly luciferase, codon optimization, in vivo gene expression, route of administration, intratracheal administration, intramuscular injection, intradermal injection, intravenous injection, intraperitoneal injection, subcutaneous injection, in vivo imaging
- MeSH terms
- Animals, Cells, Cultured, Dendritic Cells, Female, Humans, Kinetics, Lung, Mice, Inbred BALB C, Phosphatidylethanolamines, Pseudouridine, RNA, Messenger, Transfection, Luciferases, Firefly, Nanoparticles, HEK293 Cells
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