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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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“Tail chemistry can also influence the ability of a lipid to destabilize a cellular or endosomal membrane thus modifying rate of endosomal retention and release (25, 30).”
BackgroundSelf-citationElia, U., Ramishetti, S., Rosenfeld, R., Dammes, N., Bar‐Haim, E., Naidu, G. S., Makdasi, E., Yahalom-Ronen, Y., Tamir, H., Paran, N., et al. (2021) · ACS Nano · doi:10.1021/acsnano.0c10180 · Cited by 100
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“Several groups have capitalized on this property of cationic lipid formulations for siRNA delivery [14,15], using both natural and synthetic lipids to facilitate cellular entry via endocytosis or membrane fusion [16].”
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Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery
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“A very popular CIL, used to encapsulate short interfering (si)RNA, is hepta-triaconta-6,9,28,31-tetraen-19-y14-(dimethylamino) butanoate[22]alsoknownasDLin-MC3-DMA or simply MC3.”
BackgroundOmo‐Lamai, S., Wang, Y., Patel, M. N., Milosavljevic, A., Zuschlag, D. W., Poddar, S., Wu, J., Wang, L., Dong, F., Espy, C. L., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-025-01974-5 · Cited by 170
“Our primary screen evaluated 15 of the most studied and potent ionizable lipids 25,36 .”
Versatile Site-Specific Conjugation of Small Molecules to siRNA Using Click Chemistry
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“A prime example is the recent attempt in the rational design of cationic lipids for safe and effective delivery of siRNA to the liver.17 Cationic lipoplexes and polyplexes efficiently condense nucleic acids and act as powerful nonviral transfectants,18,19 but the cationic nature of the lipid or the polymeric component…”
BackgroundInfluentialNanocarrier vaccines for SARS-CoV-2
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Lipid Nanoparticle Spherical Nucleic Acids for Intracellular DNA and RNA Delivery
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Extracellular vesicles versus lipid nanoparticles for the delivery of nucleic acids
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Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC
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“formulation procedure as previously described (24).”
Self-citationMessenger RNA Delivery for Tissue Engineering and Regenerative Medicine Applications
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“Over the years, better understanding of the necessities in the delivery process has allowed the development of potent synthetic lipids leading to higher efficacy and lower toxicity.(106) The greatest advancements for in vivo delivery of nucleic acids have come in the form of ionizable lipids (e.”
Background‘Passive’ nanoparticles for organ-selective systemic delivery: design, mechanism and perspective
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Therapeutic and Safety Considerations of Nanoparticle-Mediated Drug Delivery in Pregnancy
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Therapeutic targeting in the silent era: advances in non-viral siRNA delivery
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“siRNA has been recently designed using cationic lipids [169] .”
BackgroundInfluentialDesign and evaluation of new pH-sensitive amphiphilic cationic lipids for siRNA delivery
Malamas, A. S., Gujrati, M. D., Kummitha, C. M., Xu, R., & Lu, Z. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.06.019 · Cited by 97
“Cone-shaped cationic lipids have the ability to interact with anionic phospholipids in the endosomal membrane and form ion pairs that adopt non-bilayer structures with the ability to induce bilayer disruption in these compartments [38].”
BackgroundOn the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device
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“Liposomes constituted by phospholipids [14,15], lipidoid or lipid nanoparticles [16,17], cationic lipids [18] and cationic polymers [12,19] are the most frequently used non-viral vectors for nucleic acids transfection.”
BackgroundThermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia
Hu, B., Li, B., Li, K., Liu, Y., Li, C., Zheng, L., Zhang, M., Yang, T., Guo, S., Dong, X., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm1418 · Cited by 95
“Among them, lipid nanoparticles (LNPs) are one of the most successful delivery systems because of their mature industrial manufacture technology, high cellular uptake, low cell toxicity, and low immunogenicity ( 18 , 28 – 33 ).”
InfluentialZhang, C., Ma, Y., Zhang, J., Kuo, J. C., Zhang, Z., Xie, H., Zhu, J., & Liu, T. (2022) · Molecules · doi:10.3390/molecules27061943 · Cited by 95
“However, in some cases, it is hard to process drug release and endosomal escape due to less fusion with an anionic lipid membrane [150].”
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“…example, over 60 rationally designed cationic lipids were synthesized by standard organic chemistry and tested in vivo for years before elucidating valuable structural criteria and identifying the MC3 lipid that was later approved by the Food and Drug Administration (FDA) for siRNA delivery 15,16 .”
MethodHypoxia-responsive ionizable liposome delivery siRNA for glioma therapy
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“11,15 Furthermore, compared with DLP, the zeta potential of MLP increased significantly under hypoxia, indicating that the nitroimidazole groups of MLP are converted to aminoimi-dazoles and become positively charged.”
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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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