Irf5 siRNA-loaded biodegradable lipid nanoparticles ameliorate concanavalin A-induced liver injury
| Autor: | Tatsuma Ban, Daisuke Kurotaki, Kappei Tsukahara, Hiroshi Ishihara, Tadatsugu Taniguchi, Hideyuki Yanai, Wataru Kawase, Tomohiko Tamura, Go R. Sato, Yuta Suzuki, Juri Ichikawa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Small interfering RNA
medicine.medical_treatment RM1-950 Pharmacology lipid nanoparticles Immune system RNA interference IRF5 Drug Discovery medicine Gene silencing drug delivery system hepatitis Liver injury biology Chemistry medicine.disease macrophages Cytokine Concanavalin A siRNA biology.protein Molecular Medicine Cytokine secretion Original Article Therapeutics. Pharmacology |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 25, Iss, Pp 708-715 (2021) |
| ISSN: | 2162-2531 |
| Popis: | RNA interference-based gene silencing drugs are attracting attention for treating various diseases. Lipid nanoparticles (LNPs) are carriers that efficiently deliver small interfering RNA (siRNA) to the cytoplasm of target cells. Recently, we developed potent and well-tolerated biodegradable LNPs with asymmetric ionizable lipids. Here, we evaluated the effect of LNPs on immune cells in mice. After intravenous administration, LNPs were efficiently incorporated into several tissue-resident macrophages, including liver macrophages, through an apolipoprotein E (ApoE)-independent mechanism. Administration of LNP-encapsulated siRNA against Irf5, encoding the transcription factor critical for inflammatory responses, sharply reduced its expression in macrophages in vivo, and persisted for as long as 7 days. The therapeutic potential of Irf5 siRNA-loaded LNPs in inflammatory diseases was tested in a concanavalin A (Con A)-induced hepatitis model, whose pathogenic mechanisms are dependent on cytokine secretion from macrophages. We found that Con A-induced liver injury was significantly attenuated after LNP injection. Serum aspartate transaminase, alanine aminotransferase, and inflammatory cytokine levels were significantly reduced in mice injected with Irf5 siRNA-loaded LNPs compared to those injected with control siRNA-loaded LNPs. Our results suggest that administering biodegradable LNPs to deliver siRNA is a promising strategy for treating inflammatory disorders. Graphical abstract Kawase et al. report that ionizable lipid-based biodegradable LNPs are effectively incorporated into macrophages in vivo. Administration of LNP-encapsulated siRNA against Irf5, encoding a transcription factor mediating inflammatory responses, resulted in long-term IRF5 downregulation in liver macrophages and prevented cytokine production and liver damage in a hepatitis model. |
| Databáze: | OpenAIRE |
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