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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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Comprehensive analysis of lipid nanoparticle formulation and preparation for RNA delivery
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“Commonly used helper lipids for nucleic acid delivery include DSPC, DPPC, HSPC, DOPC, POPC, SOPC, for phosphati-dylcholines, and DOPE, POPE, SOPE, for phosphatidylethanolamines ( ´ et al., 2022; Ball et al., 2018b; Jung et al., 2022; Semple et al., 2010; Zatsepin et al., 2016; Zuhorn et al., 2005).”
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An Amino Acid-based Amphoteric Liposomal Delivery System for Systemic Administration of siRNA
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Diaminododecane-based cationic bolaamphiphile as a non-viral gene delivery carrier
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MicroRNAs in dysfunctional adipose tissue: cardiovascular implications
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“159 Cholesterol analogs have been added to anti-miRs to facilitate cellular uptake, particularly in the liver, and this enhances their incorporation into HDL and LDL.160 1030 B. Icli and M.W. Feinberg D ow nloaded from https://academ ic.oup.com /cardiovascres/article-abstract/113/9/1024/3827772 by guest on 15 M arch 2…”
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Self‐Assembled Nanocarrier Delivery Systems for Bioactive Compounds
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Advances in functional lipid nanoparticles: from drug delivery platforms to clinical applications
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“When a specific siRNA enters the cell cytoplasm, it is precisely engineered to silence a single gene, thus more absorption into tissue that is not the target, which might not articulate that gene, may have only a minimal effect (Semple et al. 2010; Yan et al. 2005; Akinc et al. 2010).”
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“…that the addition of a charged polyanion with acidic carboxylic groups may change the apparent pKa of the LLNP. Prior work optimizing ionizable lipids has demonstrated that the apparent pKa of the LNP impacts its transfection potency, immunogenicity, and targeting in vivo (18, 28, 33–35).”
Steering the course of CAR T cell therapy with lipid nanoparticles
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“…a significant research has shown improved endosomal escape post-modification of lipid components in LNPs, for instance, adding cationic lipids [157], incorporating DOPE, more content of ionic lipids and mRNA size ratios [117], and replacing the lipids with those which are highly expressed in…”
BackgroundAdvances in the design and delivery of RNA vaccines for infectious diseases
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Toward personalized cancer nanomedicine – past, present, and future
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Self-citationFluorocarbon Modified Low-Molecular-Weight Polyethylenimine for siRNA Delivery
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“Our primary screen evaluated of 15 of the most studied and potent ionizable lipids 25,36 .”
Computational design of mRNA vaccines
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Neutral Polymeric Micelles for RNA Delivery
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Delivering Colloidal Nanoparticles to Mammalian Cells: A Nano–Bio Interface Perspective
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“Although numerous tumor therapeutic siRNA delivery carriers have been developed based on cationic polymers, cationic lipids, or amino acids that efficiently bind anionic RNAi, such as small interfering RNA (siRNA) and microRNA (miRNA) (6-9), these strong cationic carriers cause destabilization of cell membranes and se…”
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pH-Triggered Nanoparticle Mediated Delivery of siRNA to Liver Cells in Vitro and in Vivo
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Galactose-Modified Cationic Liposomes as a Liver-Targeting Delivery System for Small Interfering RNA
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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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