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

• Published in: Biological & pharmaceutical bulletin 2019/02/01, Vol.42(2), pp.299-302
• Main Authors: Ohto, Takara, Konishi, Manami, Tanaka, Hiroki, Onomoto, Koji, Yoneyama, Mitsutoshi, Nakai, Yuta, Tange, Kota, Yoshioka, Hiroki, Akita, Hidetaka
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Cell Line; Cyclohexylamines - pharmacology; Dexamethasone; Dexamethasone - pharmacology; Embryo fibroblasts; Fibroblasts; Immune response; Immunology; Inflammation; integrated stress response; Intravenous administration; lipid nanoparticle; Lipids; Lipids - administration & dosage; Lipids - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; mRNA; mRNA delivery; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Protein folding; RNA, Messenger - administration & dosage; Steroids; Transfection; Transfection - methods
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b18-00783

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.