ArticleMolecular therapy : the journal of the American Society of Gene Therapy2011
Mechanistically probing lipid-siRNA nanoparticle-associated toxicities identifies Jak inhibitors effective in mitigating multifaceted toxic responses.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 72 citations in OpenAlex.
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- Inhalable perfluorocarbon RNA nanocapsules overcome biological barriers to treat lung metastases.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Gelatin and lipidoid integrate to createBioactive materials · 2024Article
- siRNA-mediated reduction of a circulating protein in swine using lipid nanoparticles.Molecular therapy. Methods & clinical development · 2024Article
- Strategies to reduce the risks of mRNA drug and vaccine toxicity.Nature reviews. Drug discovery · 2024Review
- Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design.Acta pharmaceutica Sinica. B · 2024Review
- Drug delivery systems for CRISPR-based genome editors.Nature reviews. Drug discovery · 2023Review
- A holistic analysis of the intrinsic and delivery-mediated toxicity of siRNA therapeutics.Advanced drug delivery reviews · 2023Review
- SIC50: Determining drug inhibitory concentrations using a vision transformer and an optimized Sobel operator.Patterns (New York, N.Y.) · 2023Article
- Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.Journal of controlled release : official journal of the Controlled Release Society · 2023Article
- Recent Advances in Lipid Nanoparticles for Delivery of mRNA.Pharmaceutics · 2022Review
- Messenger RNA-Based Vaccines Against Infectious Diseases.Current topics in microbiology and immunology · 2022Review
- The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory.iScience · 2021Article
- Lipids and Lipid Derivatives for RNA Delivery.Chemical reviews · 2021Review
- Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein.Molecular therapy. Nucleic acids · 2021Article
- Pleiotropic Effects of Bacterial Small Alarmone Synthetases: Underscoring the Dual-Domain Small Alarmone Synthetases inFrontiers in microbiology · 2020Review
- Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles.Molecular pharmaceutics · 2019Article
- The Effect of Superparamagnetic Iron Oxide Nanoparticle Surface Charge on Antigen Cross-Presentation.Nanoscale research letters · 2017Article
- Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA.Molecular therapy. Nucleic acids · 2017Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A major hurdle for harnessing small interfering RNA (siRNA) for therapeutic application is an effective and safe delivery of siRNA to target tissues and cells via systemic administration. While lipid nanoparticles (LNPs) composed of a cationic lipid, poly-(ethylene glycol) lipid and cholesterol, are effective in delivering siRNA to hepatocytes via systemic administration, they may induce multi-faceted toxicities in a dose-dependent manner, independently of target silencing. To understand the underlying mechanism of toxicities, pharmacological probes including anti-inflammation drugs and specific inhibitors blocking different pathways of innate immunity were evaluated for their abilities to mitigate LNP-siRNA-induced toxicities in rodents. Three categories of rescue effects were observed: (i) pretreatment with a Janus kinase (Jak) inhibitor or dexamethasone abrogated LNP-siRNA-mediated lethality and toxicities including cytokine induction, organ impairments, thrombocytopenia and coagulopathy without affecting siRNA-mediated gene silencing; (ii) inhibitors of PI3K, mammalian target of rapamycin (mTOR), p38 and IκB kinase (IKK)1/2 exhibited a partial alleviative effect; (iii) FK506 and etoricoxib displayed no protection. Furthermore, knockout of Jak3, tumor necrosis factor receptors (Tnfr)p55/p75, interleukin 6 (IL-6) or interferon (IFN)-γ alone was insufficient to alleviate LNP-siRNA-associated toxicities in mice. These indicate that activation of innate immune response is a primary trigger of systemic toxicities and that multiple innate immune pathways and cytokines can mediate toxic responses. Jak inhibitors are effective in mitigating LNP-siRNA-induced toxicities.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.