Bundling of mRNA strands inside polyion complexes improves mRNA delivery efficiency in vitro and in vivo

RNA nanotechnology has promise for developing mRNA carriers with enhanced physicochemical and functional properties. However, the potential synergy for mRNA delivery of RNA nanotechnology in cooperation with established carrier systems remains unknown. This study proposes a combinational system of R...

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Published inBiomaterials Vol. 261; p. 120332
Main Authors Koji, Kyoko, Yoshinaga, Naoto, Mochida, Yuki, Hong, Taehun, Miyazaki, Takuya, Kataoka, Kazunori, Osada, Kensuke, Cabral, Horacio, Uchida, Satoshi
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier Ltd 01.12.2020
Subjects
Animals
Mice
Micelles
mRNA therapeutics
Polyethylene Glycols
Polyion complex
Polymers
Polyplex micelle
RNA nanotechnology
RNA, Messenger - genetics
Transfection
RNA nanotechnology
mRNA therapeutics
Polyplex micelle
Polyion complex
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Summary:RNA nanotechnology has promise for developing mRNA carriers with enhanced physicochemical and functional properties. However, the potential synergy for mRNA delivery of RNA nanotechnology in cooperation with established carrier systems remains unknown. This study proposes a combinational system of RNA nanotechnology and mRNA polyplexes, by focusing on mRNA steric structure inside the polyplexes. Firstly, several mRNA strands are bundled through hybridization with RNA oligonucleotide crosslinkers to obtain tight mRNA structure, and then the bundled mRNA is mixed with poly(ethylene glycol) (PEG)-polycation block copolymers to prepare PEG-coated polyplex micelles (PMs). mRNA bundling results in highly condensed mRNA packaging inside PM core with dense PEG chains on the surface, thereby, improving PM stability against polyion exchange reaction and ribonuclease (RNase) attack. Importantly, such stabilization effects are attributed to bundled structure of mRNA rather than the increase in total mRNA amount encapsulated in the PMs, as encapsulation of long mRNA strands without bundling fails to improve PM stability. Consequently, PMs loading bundled mRNA exhibit enhanced stability in mouse blood circulation, and induce efficient protein expression in cultured cells and mouse brain. [Display omitted]
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ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2020.120332