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Nat Biotechnol
. 2024 Sep 23.
doi: 10.1038/s41587-024-02393-y. Online ahead of print. Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation
Hongyu Chen # 1 2 , Dangliang Liu # 1 2 , Abhishek Aditham # 2 3 , Jianting Guo 1 2 , Jiahao Huang 1 2 , Franklin Kostas 1 2 , Kamal Maher 2 4 , Mirco J Friedrich 2 3 5 6 7 , Ramnik J Xavier 2 8 , Feng Zhang 2 3 5 6 7 , Xiao Wang 9 10 11
Affiliations
Protein and vaccine therapies based on mRNA would benefit from an increase in translation capacity. Here, we report a method to augment translation named ligation-enabled mRNA-oligonucleotide assembly (LEGO). We systematically screen different chemotopological motifs and find that a branched mRNA cap effectively initiates translation on linear or circular mRNAs without internal ribosome entry sites. Two types of chemical modification, locked nucleic acid (LNA) N7-methylguanosine modifications on the cap and LNA + 5 × 2' O-methyl on the 5' untranslated region, enhance RNA-eukaryotic translation initiation factor (eIF4E-eIF4G) binding and RNA stability against decapping in vitro. Through multidimensional chemotopological engineering of dual-capped mRNA and capped circular RNA, we enhanced mRNA protein production by up to tenfold in vivo, resulting in 17-fold and 3.7-fold higher antibody production after prime and boost doses in a severe acute respiratory syndrome coronavirus 2 vaccine setting, respectively. The LEGO platform opens possibilities to design unnatural RNA structures and topologies beyond canonical linear and circular RNAs for both basic research and therapeutic applications.
. 2024 Sep 23.
doi: 10.1038/s41587-024-02393-y. Online ahead of print. Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation
Hongyu Chen # 1 2 , Dangliang Liu # 1 2 , Abhishek Aditham # 2 3 , Jianting Guo 1 2 , Jiahao Huang 1 2 , Franklin Kostas 1 2 , Kamal Maher 2 4 , Mirco J Friedrich 2 3 5 6 7 , Ramnik J Xavier 2 8 , Feng Zhang 2 3 5 6 7 , Xiao Wang 9 10 11
Affiliations
- PMID: 39313647
- DOI: 10.1038/s41587-024-02393-y
Protein and vaccine therapies based on mRNA would benefit from an increase in translation capacity. Here, we report a method to augment translation named ligation-enabled mRNA-oligonucleotide assembly (LEGO). We systematically screen different chemotopological motifs and find that a branched mRNA cap effectively initiates translation on linear or circular mRNAs without internal ribosome entry sites. Two types of chemical modification, locked nucleic acid (LNA) N7-methylguanosine modifications on the cap and LNA + 5 × 2' O-methyl on the 5' untranslated region, enhance RNA-eukaryotic translation initiation factor (eIF4E-eIF4G) binding and RNA stability against decapping in vitro. Through multidimensional chemotopological engineering of dual-capped mRNA and capped circular RNA, we enhanced mRNA protein production by up to tenfold in vivo, resulting in 17-fold and 3.7-fold higher antibody production after prime and boost doses in a severe acute respiratory syndrome coronavirus 2 vaccine setting, respectively. The LEGO platform opens possibilities to design unnatural RNA structures and topologies beyond canonical linear and circular RNAs for both basic research and therapeutic applications.