Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
Open accessAbstract
Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2(named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore,siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion,Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.
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The main off-target site of LNP-based platforms is the liver, more specifically hepatocytes and Kupffer cells.
“The main off-target site of LNP-based platforms is the liver, more specifically hepatocytes and Kupffer cells (49, 50), and suppression of mRNAs in these cell types can be achieved by inserting miR122 and miR142 binding sites, respectively.”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [50]
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References 31 · Cited by 53
- Authors
- Woitok, M. M., Zoubek, M. E., Doleschel, D., Bartneck, M., Mohamed, M. R., Kießling, F., Lederle, W., Trautwein, C., & Cubero, F. J.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Maastricht University Medical Centre (NL)
- Universidad Complutense de Madrid (ES)
- Corresponding author
- Trautwein, Christian
- Cubero, Francisco Javier
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2020-05-11
- Volume
- 11
- Issue
- 5
- Pages
- 343-343
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC7214425
- OpenAlex
- W3021612557
- Cited by
- 53
- References
- 31
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 10 · 2023: 10 · 2022: 6 · 2021: 5 · 2020: 1
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Funders
- Deutsche Forschungsgemeinschaft (i3tm SF_15-5-17)
- ERAB: The European Foundation for Alcohol Research (EA 18/14)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- siRNA, lipid-based nanocarriers, chronic liver disease, liver fibrosis, hepatocellular carcinoma, hepatocarcinogenesis, siRNA delivery, immune cell activation, apoptosis, liver cancer
- MeSH terms
- RNAi Therapeutics, Animals, Cell Line, Cell Transformation, Neoplastic, Disease Models, Animal, Lipids, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Inbred C57BL, Apoptosis, Gene Transfer Techniques, Mice, Knockout, Hepatocytes, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 9, Nanoparticles
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