Bundling mRNA Strands to Prepare Nano‐Assemblies with Enhanced Stability Towards RNase for In Vivo Delivery. (3rd July 2019)

• Record Type: Journal Article
• Authors: Yoshinaga, Naoto; Cho, Eol; Koji, Kyoko; Mochida, Yuki; Naito, Mitsuru; Osada, Kensuke; Kataoka, Kazunori; Cabral, Horacio; Uchida, Satoshi
• Is Part Of: Angewandte Chemie. Volume 131:Number 33(2019)
• Page Start: 11482
• Page End: 11485
• Publication Date: 2019-07-03
• Subjects: Gentechnik -- mRNA -- Ribonuclease -- RNA-Strukturen -- Wirkstoff-Transport; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201905203
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Ribonuclease (RNase)‐mediated degradation of messenger RNA (mRNA) poses a huge obstruction to in vivo mRNA delivery. Herein, we propose a novel strategy to protect mRNA by structuring mRNA to prevent RNase attack through steric hinderance. Bundling of mRNA strands through hybridization of RNA oligonucleotide linkers allowed the preparation of mRNA nano‐assemblies (R‐NAs) comprised of 7.7 mRNA strands on average, mostly below 100 nm in diameter. R‐NA formation boosted RNase stability by around 100‐fold compared to naïve mRNA and preserved translational activity, allowing protein production. A mechanistic analysis suggests that an endogenous mRNA unwinding mechanism triggered by 5′‐cap‐dependent translation may induce selective R‐NA dissociation intracellularly, leading to smooth translation. R‐NAs showed efficient mRNA transfection in mouse brain, demonstrating the feasibility for in vivo administration. Abstract : Gebündelte Informationen : Durch Hybridisierung mit RNA‐Oligonukleotid‐Linkern wurden mRNAs zu Nanoanordnungen (R‐NAs) gebündelt, was in einer erhöhten Stabilität gegen RNase unter Beibehaltung der Translationsaktivität resultierte. Die R‐NAs konnten ohne Einsatz eines Transfektionsreagens ins Maushirn transportiert werden. Diese Strategie könnte die Effizienz mRNA‐basierter Therapeutika verbessern.