Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA
Open accessAbstract
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.
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Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, but they have had varied success.
“Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, including cationic nanoemulsions109,161, DOTAP/DOPE liposomes162, polymers84,163,164 and ionizable LNPs165,166, but they have had varied success.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [165]
Novel antigens are necessary to effectively target HIV in addition to potent delivery vehicles.
“These studies suggest that novel antigens are necessary to effectively target HIV in addition to potent delivery vehicles.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [165]
This structural feature protects mRNA molecules from nuclease degradation and increases nanoparticle stability in physiological fluids.
“This structural feature protects mRNA molecules from nuclease degradation and increases nanoparticle stability in physiological fluids17,46.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [46]
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- Authors
- Blakney, A. K., McKay, P. F., Yus, B. I., Aldon, Y., & Shattock, R. J.
- Affiliations
- Imperial College London (GB)
- Corresponding author
- Shattock, Robin J.
- Venue
- Gene Therapy
- Published
- 2019-07-12
- Volume
- 26
- Issue
- 9
- Pages
- 363-372
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC6760535
- OpenAlex
- W2961919374
- Cited by
- 206
- References
- 37
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 30 · 2023: 38 · 2022: 37 · 2021: 32 · 2020: 23 · 2019: 2
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Gene Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Whitaker Foundation
- European Commission (794059, 681137)
- RCUK | Engineering and Physical Sciences Research Council (EP/R013764/1)
- EC | Horizon 2020 Framework Programme (681137)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- self-amplifying RNA, lipid nanoparticles, cationic lipids, ionizable lipids, surface complexation, vaccine adjuvants, RNA encapsulation
- MeSH terms
- Quaternary Ammonium Compounds, Animals, Cations, Fatty Acids, Monounsaturated, Female, Humans, Lipids, Mice, Inbred BALB C, Particle Size, Ribonucleases, RNA, Messenger, Transfection, HIV Antibodies, RNA Stability, Luciferases, Firefly, Mice, Nanoparticles, env Gene Products, Human Immunodeficiency Virus, HEK293 Cells
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