Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics
Open accessAbstract
In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available.
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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.
“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 [43]
The Materials and Methods describe the same four lipid components but give a molar ratio of 55:10:32.5:2.5 and a total-lipid-to-siRNA weight ratio of ~10:1 (siRNA-to-lipid ~0.1), rather than the claimed 50:10:38.5:1.5 and ~0.05. The in vivo efficacy section reports a mean particle diameter of ~60 nm, not ~80 nm. No page numbers are available in our copy. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe 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 [43]
The 'In vivo efficacy evaluation in mouse FVII model' section reports siRNA-dependent gene silencing in mice and rats, and 'Efficacy and rapid elimination properties translate to higher species' reports about 70% silencing of a hepatic gene in nonhuman primates. The paper does not demonstrate hepatic gene silencing in humans or establish that the Acuitas mRNA platform was developed from this technology; its Introduction mentions human clinical trials without making those links. Our copy provides no page numbers for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEndosomal escape can be increased by optimizing the pKa values of ionizable lipids.
“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [76]
Biodegradable lipids can be applied to improve the biocompatibility of lipid nanoparticles.
“To improve the biocompatibility of lipid nanoparticles, biodegradable lipids can be applied76–78,108,179.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [76]
The delivery efficacy of mRNA could be improved by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle-mRNA formulations.
“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [76]
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- Authors
- Maier, M. A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y. K., Ansell, S. M., Kumar, V., Qin, J., Zhang, X., Wang, Q., Panesar, S., Hutabarat, R., Carioto, M., Hettinger, J., Kandasamy, P., Butler, D., Rajeev, K. G., Pang, B., Charisse, K., Fitzgerald, K., Mui, B. L., Du, X., Cullis, P., Madden, T. D., Hope, M. J., Manoharan, M., & Akinc, A.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- University of British Columbia (CA)
- Corresponding author
- Akinc, Akin
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 21
- Issue
- 8
- Pages
- 1570-1578
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3734658
- OpenAlex
- W2029397995
- Cited by
- 625
- References
- 17
- Citations by year
- 2026: 63 · 2025: 94 · 2024: 97 · 2023: 78 · 2022: 95 · 2021: 57 · 2020: 35 · 2019: 21 · 2018: 21 · 2017: 15 · 2016: 14 · 2015: 17 · 2014: 15 · 2013: 3
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alnylam Pharmaceuticals
- 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
- lipid nanoparticles, RNA interference therapy, biodegradable lipids, ionizable lipids, plasma clearance, biocompatibility, tolerability, lipid nanoparticle formulation
- MeSH terms
- Animals, Cell Line, Factor VII, Humans, Lipids, Macaca fascicularis, Male, Genetic Therapy, Drug Delivery Systems, Gene Transfer Techniques, Gene Silencing, RNA Interference, RNA, Small Interfering, Mice, Rats, Nanoparticles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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