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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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“Stable nucleic acid lipid nanoparticles (SNALP) were established specifically for encapsulating siRNA into liposomes with a lipid composition of 1,2-distearoylsn-glycero-3-phosphocholine (DSPC), cholesterol, 3-N-[(ω-methoxypoly(ethylene glycol)2000)carbamoyl]1,2-dimyristyloxy-propylamine (PEG-C-DMA), and 1,2-dilinoley…”
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Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery
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“Ionizable lipids remain neutral in circulation, avoiding cellular or molecular recognition, but become protonated and fuse with the endosomal membrane after cellular uptake, releasing the mRNA cargo into the cytoplasm for translation [11].”
BackgroundSmall RNA combination therapy for lung cancer
Xue, W., Dahlman, J. E., Tammela, T., Khan, O. F., Sood, S., Dave, A., Cai, W., Chirino, L. M., Yang, G. R., Bronson, R. T., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412686111 · Cited by 247
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“7A), which is even higher than the top reported LNP formulations (33, 61, 62).”
BackgroundNon-viral gene therapy: Gains and challenges of non-invasive administration methods
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“4%) resulted in a dramatic increase in the potency of the lipid formulation [64].”
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“Through rational design, we incorporated structural features with the potential to affect RNA endosomal escape, such as degree of unsaturation and branching 9 , into both tail components.”
Effect of mRNA-LNP components of two globally-marketed COVID-19 vaccines on efficacy and stability
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“Further, they are protonated in the acidic endosome after cellular uptake and thus interact with anionic endosomal phospholipids to form cone-shaped ion pairs that facilitate membrane fusion and disruption, endosomal escape, and cargo release into the cytosol 40,41 .”
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Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach
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“82 While anionic liposomes are usually cleared from circulation, cationic liposomes (eg, DC-Cholesterol, DOTAP, and AtuFECT01 among others) in combination with helper lipids (eg, Cholesterol, DOPE, and DPhyPE) have proved ef fi cient in siRNA delivery at optimized N/ P ratios.”
Advances in lipid nanoparticles for siRNA delivery
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“injection, which is currently the worldwide gold standard for siRNA-based therapeutics [13,14].”
BackgroundSelf-citationpH-Responsive Polymeric Micelle Carriers for siRNA Drugs
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Design of lipid nanoparticles for in vitro and in vivo delivery of plasmid DNA
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“It is well established that the species of amino-lipid can strongly affect the gene silencing potencies of LNP (7, 15).”
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“4) become positively charged in the endosomes facilitating their interaction with and thereby disruption of the endosomal membrane [40].”
BackgroundProgress Toward In Vivo Use of siRNAs-II
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“169 These new highly potent lipid formulations primarily target liver; finding formulations that provide similar high potency delivery to other tissues remains an area of active investigation.”
Nanoparticles Escaping RES and Endosome: Challenges for siRNA Delivery for Cancer Therapy
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“[131] developed DLinDMA derivatives by optimizing the headgroup and linker moiety to formulate stable nucleic acidlipid particles (SNALPs).”
Method
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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