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Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
Open accessAbstract
siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
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“The delivery of therapeutic RNA molecules (siRNA or microRNA) encapsulated within the lipid or lipid-like carrier231,232 into the cells or tissues was proven to be effective in infectious diseases and tumors, as shown in many preclinical studies233,234,235 and clinical trials (reviewed by Kaczmarek et al.236).”
From MiR-128-3p – a gray eminence of the human central nervous system (2024) · cites this paper as [233]
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“Some other LNPs were reported with organ specificity, such as cKK-E12 lipopeptide nanoparticles, wherein the lipid tails were conjugated to peptide derivatives and achieved liver targeting siRNA delivery.[67]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [67]
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Metadata
- Authors
- Dong, Y., Love, K. T., Dorkin, J. R., Sirirungruang, S., Zhang, Y., Chen, D., Bogorad, R. L., Yin, H., Chen, Y., Vegas, A. J., Alabi, C. A., Sahay, G., Olejnik, K. T., Wang, W., Schroeder, A., Lytton-Jean, A. K. R., Siegwart, D. J., Akinc, A., Barnes, C., Barros, S. A., Carioto, M., Fitzgerald, K., Hettinger, J., Kumar, V., Novobrantseva, T. I., Qin, J., Querbes, W., Koteliansky, V., Langer, R., & Anderson, D. G.
- Affiliations
- Boston Children's Hospital (US)
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
- Alnylam Pharmaceuticals (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-10
- Volume
- 111
- Issue
- 11
- Pages
- 3955-3960
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3964096
- OpenAlex
- W2071030419
- Cited by
- 488
- References
- 35
- Citations by year
- 2026: 29 · 2025: 45 · 2024: 53 · 2023: 51 · 2022: 40 · 2021: 42 · 2020: 35 · 2019: 30 · 2018: 29 · 2017: 39 · 2016: 41 · 2015: 36 · 2014: 17
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-03-26)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Alnylam Pharmaceuticals
- National Institutes of Health (5r01de016516-10, 4r37eb000244-34, 5-R01-, 1f32eb017625-01, 5r01ca132091-04, CA151884, DE-016516, U54-CA151884, EB-000244, R01-EB000244-27, DE016516-03)
- National Heart, Lung, and Blood Institute (HHSN268201000045C)
- National Cancer Institute (5-R01-CA132091–04, U54CA151884, CA151884, R01-CA132091)
- National Institute of Biomedical Imaging and Bioengineering (R01-EB000244-27, EB-000244, R01EB000244, R37-EB000244, 1F32EB017625, F32 EB017625)
- National Institute of Dental and Craniofacial Research (R01DE016516-03)
- 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, apolipoprotein E, hepatocyte targeting, liver parenchymal cells, siRNA therapeutics, toxicity, rodents, non-human primates, lipoproteins
- MeSH terms
- Animals, Apolipoproteins E, Macaca fascicularis, Drug Delivery Systems, Cryoelectron Microscopy, Gene Silencing, Hepatocytes, RNA, Small Interfering, Mice, Rats, Nanoparticles, Lipopeptides
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