Inhibition of the Inflammatory Pathway Enhances Both the <i>in Vitro</i> and <i>in Vivo</i> Transfection Activity of Exogenous <i>in Vitro</i>-Transcribed mRNAs Delivered by Lipid Nanoparticles

• Ohto Takara

  Graduate School of Pharmaceutical Sciences, Chiba University

• Konishi Manami

  Graduate School of Pharmaceutical Sciences, Chiba University

• Tanaka Hiroki

  Graduate School of Pharmaceutical Sciences, Chiba University

• Onomoto Koji

  Division of Molecular Immunology, Medical Mycology Research Center

• Yoneyama Mitsutoshi

  Division of Molecular Immunology, Medical Mycology Research Center

• Nakai Yuta

  DDS Research Laboratory, DDS Development Division, NOF CORPORATION

• Tange Kota

  DDS Research Laboratory, DDS Development Division, NOF CORPORATION

• Yoshioka Hiroki

  DDS Research Laboratory, DDS Development Division, NOF CORPORATION

• Akita Hidetaka

  Graduate School of Pharmaceutical Sciences, Chiba University

Bibliographic Information

Other Title

• Inhibition of the Inflammatory Pathway Enhances Both the in Vitro and in Vivo Transfection Activity of Exogenous in Vitro-Transcribed mRNAs Delivered by Lipid Nanoparticles

Abstract

While the use of in vitro-transcribed mRNA (IVT-mRNA) in therapeutics is a rapidly expanding area, the transfection of the exogenous IVT-mRNA is accompanied by a risk of immune activation. This immunological defense mechanism suppresses cellular translation process and can reduce transfection efficiency to a considerable extent. In the present study, we investigated the in vitro effects of Integrated Stress Response Inhibitor (ISRIB), and dexamethasone, a steroidal anti-inflammatory drug, on the transfection activity of a lipid nanoparticle (LNP) that was composed of ionizable lipids and IVT-mRNA. In the case of transfection to mouse embryonic fibroblast (MEF) cells, ISRIB mainly enhanced the transfection activity at an early stage of transfection (0–6 h). In contrast, dexamethasone caused an increase in transfection activity at intermediate-late stages of transfection (4–48 h). We also investigated the in vivo effects of dexamethasone using an LNP on that the IVT-mRNA and lipid-conjugated dexamethasone (Dex-Pal) were co-loaded. The intravenous administration of the LNP successfully enhanced the protein expression in a mouse liver by up to 6.6-fold. Collectively, the co-delivery of an anti-inflammatory drug is a promising approach for enhancing transfection efficiency of IVT-mRNA.

Journal

• Biological and Pharmaceutical Bulletin

  Biological and Pharmaceutical Bulletin 42 (2), 299-302, 2019-02-01

  The Pharmaceutical Society of Japan

Keywords

• mRNA delivery
• lipid nanoparticle
• integrated stress response
• inflammation
• dexamethasone

Details

• CRID: 1390564238074655104
• NII Article ID: 130007587594
• NII Book ID: AA10885497
• DOI: 10.1248/bpb.b18-00783
• ISSN: 13475215
• ISSN: 09186158
• NDL BIB ID: 029482220
• PubMed: 30713260
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I029482220
• Web Site: https://www.jstage.jst.go.jp/article/bpb/42/2/42_b18-00783/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2019253975
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed