An ionizable lipid toolbox for RNA delivery
Open accessAbstract
Recent years have witnessed incredible growth in RNA therapeutics, which has benefited significantly from decades of research on lipid nanoparticles, specifically its key component—the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development. RNA therapeutics have benefited significantly from decades of research on lipid nanoparticles, specifically its key component—the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development.
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LNPs have an ionizable lipid that is predominantly neutral at physiological pH, unlike the quaternary lipid DOTMA, allowing an excellent combination of in vivo efficacy and low toxicity.
“In addition, LNPs have an ionizable lipid, which is predominantly neutral at physiological pH, as opposed to the quaternary lipid DOTMA, and this allows them to have an excellent combination of in vivo efficacy and low toxicity (8, 13).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [13]
The Biodegradable ionizable lipids section (page unavailable) describes an ionizable lipid with robust in vivo gene silencing and lower toxicity, and another that maintained potency with improved tolerability. Our copy does not establish the comparison with DOTMA or say that being predominantly neutral at physiological pH causes the claimed combination of efficacy and low toxicity. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIonizable lipid nanoparticles (LNPs) are a promising non-viral delivery platform for mRNA nanomedicines and have been used to deliver siRNA and CRISPR-based gene editing therapies to the liver in postnatal mouse, non-human primate, and clinical studies with encouraging results.
“Ionizable lipid nanoparticles (LNPs) are a promising non-viral delivery platform for mRNA nanomedicines (13, 14) that have been used to deliver siRNA and CRISPR-based gene editing therapies to the liver in postnatal mouse, non-human primate, and clinical studies with encouraging results (15–18).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [18]
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Experimental — accuracy not yet measuredThe ideal N:P ratio is distinct for each ionizable lipid.
“The ideal N:P ratio is known to be distinct for each ionizable lipid (18).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [18]
The Multi-tail ionizable lipids section discusses optimizing LNP composition, but does not identify an ideal N:P ratio or say that it differs for each ionizable lipid. Searches for N:P, nitrogen-to-phosphate ratio, and lipid-specific charge-ratio optimization found no passage addressing that point; page numbers were unavailable in our copy. (LLM, conf=0.74)
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Self-citationLipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
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- Authors
- Han, X., Zhang, H., Butowska, K., Swingle, K. L., Alameh, M.-G., Weissman, D., & Mitchell, M. J.
- Affiliations
- University of Pennsylvania (US)
- University of Gdańsk (PL)
- Abramson Cancer Center (US)
- Corresponding author
- Mitchell, Michael J.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-12-13
- Volume
- 12
- Issue
- 1
- Pages
- 7233-7233
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8668901
- OpenAlex
- W4200599268
- Cited by
- 628
- References
- 18
- Citations by year
- 2026: 133 · 2025: 177 · 2024: 169 · 2023: 105 · 2022: 44
- FWCI
- 24.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (DP2 TR002776)
- National Science Foundation (Graduate Research Fellowship)
- 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
- ionizable lipids, lipid nanoparticles, RNA delivery, RNA therapeutics, lipid nanoparticle formulation
- MeSH terms
- Drug Development, Humans, Ions, Lipids, Endosomes, RNA, Drug Delivery Systems, Nanoparticles
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