Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity
Open accessAbstract
One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure-function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg(-1)). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.
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Endosomal escape can be increased by optimizing the pKa values of ionizable lipids.
“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [88]
The delivery efficacy of mRNA could be improved by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle-mRNA formulations.
“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [88]
LNPs represent a major intravenously administered siRNA delivery system for clinical applications.
“Among the reported non-viral siRNA delivery platforms, LNPs represent a major intravenously (i.v.) administered siRNA delivery system for clinical applications.[22, 38]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [38]
All these lipid materials showed improved delivery efficiency compared with DLin-KC2-DMA LNPs.
“All these lipid materials showed improved delivery efficiency as compared with DLin-KC2-DMA LNPs.[38, 64, 65]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [38]
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Self-citation
- Authors
- Whitehead, K. A., Dorkin, J. R., Vegas, A. J., Chang, P. H., Veiseh, O., Matthews, J., Fenton, O. S., Zhang, Y., Olejnik, K. T., Yesilyurt, V., Chen, D., Barros, S., Klebanov, B., Novobrantseva, T., Langer, R., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts Institute of Technology (US)
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Anderson, Daniel G.
- ORCID
- Venue
- Nature Communications
- Published
- 2014-06-27
- Volume
- 5
- Issue
- 1
- Pages
- 4277-4277
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4111939
- OpenAlex
- W2000071382
- Cited by
- 615
- References
- 44
- Citations by year
- 2026: 45 · 2025: 63 · 2024: 79 · 2023: 67 · 2022: 47 · 2021: 54 · 2020: 46 · 2019: 48 · 2018: 50 · 2017: 31 · 2016: 47 · 2015: 28 · 2014: 8 · 2013: 1 · 2012: 1
- FWCI
- 15.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH1310215, W81XWH-13)
- Alnylam Pharmaceuticals
- National Institutes of Health (1r01ca132091-01, W81XWH, EB-000244)
- National Cancer Institute (R01CA115527, R01-CA132091)
- National Institute of Biomedical Imaging and Bioengineering (F32EB009623, EB-000244, R01EB000244, EB009623)
- Congressionally Directed Medical Research Programs (W81XWH-13-1-0215)
- 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, RNA interference therapy, structure-function relationship, transfection efficiency, pKa, hepatocytes, immune cells, chemical library screening
- MeSH terms
- Animals, Drug Carriers, Leukocytes, Lipids, Transfection, Hepatocytes, RNA, Small Interfering, Mice, Nanoparticles, Gene Knockdown Techniques
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