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Rational design of cationic lipids for siRNA delivery
Abstract
We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.
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“There are limited published data on the in vivo delivery of self-amplifying RNA using nonviral delivery strategies (3,14,18), and none has taken advantage of the recently developed, clinically suitable delivery systems for siRNA (19,20).”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [19]
In the citing paper
“Recently, there has been an exponential growth in the development of clinically suitable nonviral delivery systems for siRNA (19,20); we have taken advantage of these innovations to develop the LNP/RNA formulation and have now embarked on a more extensive evaluation of other nonviral delivery systems.”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [19]
In the citing paper
“They can also increase the transport efficiency of siRNA by lowering toxicity and enhancing biological dispersion.319”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [319]
In the citing paper
“considerable effort has been made to reduce the siRNA payload by developing different lipid formulations for delivery, which has so far led to a tenfold or even 100-fold reduction in the dose of siRNA administered to different models77,78.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [77]
In the citing paper
“Semple et al. reported that DLin-KC2-DMA containing stable nucleic acid lipid particles (SNALPs) exhibited in vivo activity at siRNA doses of 0.01 mg/kg in the mouse model and was capable of silencing the TTR gene in nonhuman primates with ED50 around 0.3 mg/kg.[63]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [63]
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“Cationic lipids (liposomes and lipid nanoparticles (LNPs)) are the most commonly used non-viral vectors for RNAi delivery, both in development and clinical trials [100,113].”
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mRNA-Based Therapeutics in Cancer Treatment
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“Lipids di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy) heptadecanedioate (L319) was synthesized as described by Maier Molecular Therapy: Nucleic Acids Vol. 32 June 2023 801 et al.,49 heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA; MC3) as described by Jayaraman et al.,47 and…”
BackgroundMethodInfluentialInfluence of ionizable lipid tail length on lipid nanoparticle delivery of mRNA of varying length
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“24 28 Organ tropisms of LNPs are also guided by ILs due to the formation of protein coronas, 29 – 33 targeted delivery to specific cell types, 34,35 and specific uptake pathways.”
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“…cholesterol (neutral lipid), dipalmitoylphosphatidylcholine (DPPC, helper lipid for nanoparticle stabilization), and N-[(methoxy poly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxlpropyl-3-amine (PEG-C-DMA lipid) used at a molar ratio of 57.1:34.3:7.1:1.4 as described by Semple et al. (2010).”
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“The carboxylic acid 3 was synthesized from benzyl 5-hexynoate (1)36 and (p-iodophenyl)acetic acid (2) by standard Sonogashira coupling.”
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Metadata
- Authors
- Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., Hafez, I. M., Dorkin, J. R., Qin, J., Lam, K., Rajeev, K. G., Wong, K. F., Jeffs, L. B., Nechev, L., Eisenhardt, M. L., Jayaraman, M., Kazem, M., Maier, M. A., Srinivasulu, M., Weinstein, M. J., Chen, Q., Alvarez, R., Barros, S. A., De, S., Klimuk, S. K., Borland, T., Kosovrasti, V., Cantley, W. L., Tam, Y. K., Manoharan, M., Ciufolini, M. A., Tracy, M. A., de Fougerolles, A., MacLachlan, I., Cullis, P. R., Madden, T. D., & Hope, M. J.
- Affiliations
- Arbutus Biopharma (Canada) (CA)
- Alnylam Pharmaceuticals (United States) (US)
- University of British Columbia (CA)
- Corresponding author
- Semple, Sean C
- Akinc, Akin
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2010-01-17
- Volume
- 28
- Issue
- 2
- Pages
- 172-176
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2083249633
- Cited by
- 1,822
- References
- 24
- Citations by year
- 2026: 124 · 2025: 165 · 2024: 175 · 2023: 145 · 2022: 145 · 2021: 119 · 2020: 90 · 2019: 102 · 2018: 83 · 2017: 85 · 2016: 95 · 2015: 85 · 2014: 105 · 2013: 103 · 2012: 98
- FWCI
- 39.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (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
- siRNA delivery, lipid nanoparticles, RNAi therapeutics, ionizable cationic lipids
- MeSH terms
- Cations, Drug Carriers, Drug Compounding, Lipids, Transfection, Drug Design, RNA, Small Interfering
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