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, and none has taken advantage of the recently developed, clinically suitable delivery systems for siRNA.
“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]
Recently, there has been an exponential growth in the development of clinically suitable nonviral delivery systems for siRNA.
“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]
Ionizable cationic lipids can increase the transport efficiency of siRNA by lowering toxicity and enhancing biological dispersion.
“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]
Considerable effort to reduce siRNA payload by developing different lipid formulations has led to a tenfold or even 100-fold reduction in the dose of siRNA administered to different models.
“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]
Semple et al. reported that DLin-KC2-DMA containing SNALPs exhibited in vivo activity at siRNA doses of 0.01 mg/kg in mouse and silenced TTR gene in nonhuman primates with ED50 around 0.3 mg/kg.
“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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“There was a statistically significant difference between groups as determined by one-way analysis of variance (F(6,14)1⁄4 86.”
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Unlocking the promise of mRNA therapeutics
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“Endosomal escape of delivered mRNA is largely dependable on interactions between ionizable lipids and naturally occurring anionic phospholipids in the endosomal membrane.(43) Prior to membrane fusion, ionizable lipids in lipid nanoparticles (LNPs) and anionic lipids in the endosomal membrane adopt a cylindrical confor…”
BackgroundIn vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight
Dahlman, J. E., Barnes, C., Khan, O. F., Thiriot, A., Jhunjhunwala, S., Shaw, T. E., Xing, Y., Sager, H. B., Sahay, G., Speciner, L., et al. (2014) · Nature Nanotechnology · doi:10.1038/nnano.2014.84 · Cited by 593 · see citing works
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Lipid nanoparticles for nucleic acid delivery: Current perspectives
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“Further optimization of the LNP-siRNA systems was achieved by increasing the lipid content to 50 mol% [8], resulting in an ED 50 for KC2 of 0.1 mg siRNA/kg with no apparent hepatic toxicities.”
InfluentialSelf-citationNanomaterial Delivery Systems for mRNA Vaccines
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“4 for the ionizable lipid DLin-MC3-DMA [92,93].”
Strategies, design, and chemistry in siRNA delivery systems
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Polymeric micelles in cancer therapy: State of the art
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Exosomes for targeted siRNA delivery across biological barriers
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Lipid Nanoparticle Technology for Clinical Translation of siRNA Therapeutics
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“A total of 1.385 mL of the lipid mixtures were placed in Slide-A-Lyzer G2 dialysis cassettes from Thermo Scientific with a molecular weight cutoff of 10 K with polyA (0.415 mL of 16.4 mg/mL polyA in water, 3:1 CIL:nucleotidemolar ratio) to a total final volume of 1.8mL.”
BackgroundInfluentialThi, T. T. H., Suys, E. J. A., Lee, J. S., Nguyen, D. H., Park, K. D., & Truong, N. P. (2021) · Vaccines · doi:10.3390/vaccines9040359 · Cited by 538 · see citing works
“The ketal linker was demonstrated to be the best candidates when compared to ester- and alkoxy-linkers [18].”
BackgroundInfluentialGold Nanoparticles for Nucleic Acid Delivery
Ding, Y., Jiang, Z., Saha, K., Kim, C. S., Kim, S. T., Landis, R. F., & Rotello, V. M. (2014) · Molecular Therapy · doi:10.1038/mt.2014.30 · Cited by 521 · see citing works
The 60-year evolution of lipid nanoparticles for nucleic acid delivery
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“DLinKC2DMA (2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane) was identified as a more potent ionizable lipid when incorporated into LNP containing siRNA to silence Factor VII (FVII) in the liver of rodents and NHPs following i.v. administration 126 .”
InfluentialSelf-citationKim, J., Eygeris, Y., Gupta, M., & Sahay, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.014 · Cited by 514 · see citing works
Recent advances in mRNA vaccine technology
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Self-citationPolymeric Nanostructures for Imaging and Therapy
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Molecular Mechanisms and Biological Functions of siRNA
Dana, H., Chalbatani, G. M., Mahmoodzadeh, H., Gharagouzloo, E., Karimloo, R., Rezaiean, O., Moradzadeh, A., Mazraeh, A., Marmari, V., Rashno, M. M., et al. (2017) · International Journal of Biomedical Science · doi:10.59566/ijbs.2017.13048 · Cited by 505 · see citing works
“Lipid-based systems include liposomes, micelles, emulsions, and solid lipid nanoparticles (108-121).”
BackgroundOptimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs
Lokugamage, M. P., Vanover, D. A., Beyersdorf, J. P., Hatit, M. Z. C., Rotolo, L., Echeverri, E. S., Peck, H. E., Ni, H., Yoon, J., Kim, Y., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00786-x · Cited by 507 · see citing works
Integrating Artificial Intelligence and Nanotechnology for Precision Cancer Medicine
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Self-assembled RNA interference microsponges for efficient siRNA delivery
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“Because both ends of the linear DNA are also partially complementary to the T7 promoter sequence, the long strand is hybridized with a short DNA strand containing the T7 promoter sequence to form circular DNA [1] (see Supplementary Table S1).”
Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
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“TTR, primarily synthesized in hepatocytes, plays significant roles in transporting thyroxine and retinol (10).”
BackgroundSelf-citationLipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy
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Extracellular vesicles as drug delivery systems: Lessons from the liposome field
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Silencing disease genes in the laboratory and the clinic
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“01 mg/kg [148]).”
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“C57BL/6 mice (Charles River Laboratories) received either PBS or siRNA in lipidoid formulations via weekly tail vein injections as previously described [13,22,23,24].”
MethodA Comprehensive Review of mRNA Vaccines
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“DLinDMA was further optimized to DLinKC2-DMA, and further to DLin-MC3-DMA depending on a series of structure–activity relationship-based studies [45,46].”
MethodNanocarriers for drug delivery applications
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Microfluidic formulation of nanoparticles for biomedical applications
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Surface-Engineered Dendrimers in Gene Delivery
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“Yet another method is using neutrally charged ionizable lipids that become positively charged inside an endosome that leads to their disruption to release the siRNA carriers [37].”
BackgroundMethodCarriers Break Barriers in Drug Delivery: Endocytosis and Endosomal Escape of Gene Delivery Vectors
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Recent progress in development of siRNA delivery vehicles for cancer therapy
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Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
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- 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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