Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo
Open accessAbstract
Special (lipid) delivery: The role of the ionizable lipid pK(a) in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK(a) range of 6.2-6.5. The most potent cationic lipid from this study has ED(50) levels around 0.005 mg kg(-1) in mice and less than 0.03 mg kg(-1) in non-human primates.
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The Acuitas mRNA delivery platform has been developed from technology shown previously to enable siRNA-dependent hepatic gene silencing across species in rodents, nonhuman primates and humans.
“The Acuitas mRNA delivery platform has been developed from technology shown previously to enable siRNA-dependent hepatic gene silencing across species in rodents, nonhuman primates and humans.28,43,44”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [28]
The study reports siRNA-mediated hepatic gene silencing in mice and cynomolgus monkeys (Figure 7; page not available). Its conclusion mentions a related formulation in a human clinical trial and preliminary LDL-C decreases, but does not demonstrate hepatic gene silencing in humans or identify the Acuitas mRNA platform as derived from this technology. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAt blood pH, LNPs exhibit a net neutral surface charge but become positively charged in acidified endosomes following ApoE-mediated endocytosis by hepatocytes in vivo, resulting in endosome disruption and release of mRNA into the cytoplasm.
“At blood pH, LNPs exhibit a net neutral surface charge but become positively charged in acidified endosomes following ApoE-mediated endocytosis by hepatocytes in vivo, resulting in endosome disruption and release of mRNA into the cytoplasm.28,41,45”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [28]
The main text around Figure 5 (page not provided) describes minimal LNP charge at blood pH, ApoE-mediated hepatocyte uptake, and positive charge in acidified endosomes promoting membrane disruption. It says siRNA, not mRNA, is released into the cytoplasm; the cited study concerns siRNA delivery. (LLM, conf=0.91)
Experimental — accuracy not yet measuredLNPs used in this study are similar in composition to those described previously, which contain an ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG-lipid (50:10:38.5:1.5 mol/mol), encapsulated RNA-to-total lipid ratio of ~0.05 (wt/wt) and a diameter of ~80 nm.
“LNPs used in this study are similar in composition to those described previously, which contain an ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG-lipid (50:10:38.5:1.5 mol/mol), encapsulated RNA-to-total lipid ratio of ~0.05 (wt/wt) and a diameter of ~80 nm.28,43”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [28]
The paper describes an optimized LNP formulation with the stated 50/10/38.5/1.5 molar composition. In its formulation description (page not available), it gives an approximately 0.05 siRNA-to-lipid ratio and a 70–90 nm particle-size range, but those measurements are stated for the earlier 40/10/40/10 formulation, not explicitly for the optimized one. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLNP systems with this lipid composition can silence target genes in hepatocytes following IV injection at dose levels as low as 0.01 mg siRNA/kg body weight in an apolipoprotein E (ApoE)-dependent fashion.
“Previous work has shown that LNP systems with this lipid composition can silence target genes in hepatocytes following IV injection at dose levels as low as 0.01 mg siRNA/kg body weight8,9 in an apolipoprotein E (ApoE)–dependent fashion.10”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [9]
If the LNP shells are permeable to protons, the pH would be similar to the rest of the formulation, around 7 to 8, meaning that most of the ionizable cationic lipids would be uncharged.
“If the LNP shells are permeable to protons –which is likely, as ionized dyes such as 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) and thionine can enter the LNP core (Jayaraman et al., 2012, Brader et al., 2021) – the pH would be similar to the rest of the formulation, around 7 to 8, meaning that most of the ionizable cationic lipids would be uncharged.”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Jayaraman et al., 2012
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Self-citation
- Authors
- Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., Rajeev, K. G., Hafez, I. M., Akinc, A., Maier, M. A., Tracy, M. A., Cullis, P. R., Madden, T. D., Manoharan, M., & Hope, M. J.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- AlCana Technologies Vancouver BC Canada
- University of British Columbia (CA)
- Corresponding author
- Jayaraman, Muthusamy
- Hope, Michael J.
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2012-07-10
- Volume
- 51
- Issue
- 34
- Pages
- 8529-8533
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC3470698
- OpenAlex
- W2106885643
- Cited by
- 1,267
- References
- 16
- Citations by year
- 2026: 121 · 2025: 151 · 2024: 165 · 2023: 141 · 2022: 134 · 2021: 141 · 2020: 88 · 2019: 59 · 2018: 49 · 2017: 39 · 2016: 52 · 2015: 49 · 2014: 50 · 2013: 24 · 2012: 4
- FWCI
- 16.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (FRN59836)
- 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
- siRNA, lipid nanoparticles, ionizable lipids, pKa, cationic lipids, siRNA delivery, non-human primates
- MeSH terms
- Amines, Animals, Female, Humans, Kinetics, Lipids, Liposomes, Liver, Mice, Inbred C57BL, Genetic Therapy, Gene Silencing, RNA, Small Interfering, Mice, Nanoparticles
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