期刊
BIOMATERIALS
卷 261, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2020.120332
关键词
RNA nanotechnology; mRNA therapeutics; Polyion complex; Polyplex micelle
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [20H04524, 18K03529, JP18K19901]
- Research and Development of Core Technologies for Gene and Cell Therapy [JP18ae0201009]
- Project for Cancer Research And Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development (AMED) [JP17cm0106202]
- Grants-in-Aid for Scientific Research [20H04524] Funding Source: KAKEN
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.
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