tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 2 [/SUP], Dangliang Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Abhishek Aditham[SUP] #[/SUP][SUP] 2 3 [/SUP], Jianting Guo[SUP] 1 2 [/SUP], Jiahao Huang[SUP] 1 2 [/SUP], Franklin Kostas[SUP] 1 2 [/SUP], Kamal Maher[SUP] 2 4 [/SUP], Mirco J Friedrich[SUP] 2 3 5 6 7 [/SUP], Ramnik J Xavier[SUP] 2 8 [/SUP], Feng Zhang[SUP] 2 3 5 6 7 [/SUP], Xiao Wang[SUP] 9 10 11 [/SUP]
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) N[SUP]7[/SUP]-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[SUP] #[/SUP][SUP] 1 2 [/SUP], Dangliang Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Abhishek Aditham[SUP] #[/SUP][SUP] 2 3 [/SUP], Jianting Guo[SUP] 1 2 [/SUP], Jiahao Huang[SUP] 1 2 [/SUP], Franklin Kostas[SUP] 1 2 [/SUP], Kamal Maher[SUP] 2 4 [/SUP], Mirco J Friedrich[SUP] 2 3 5 6 7 [/SUP], Ramnik J Xavier[SUP] 2 8 [/SUP], Feng Zhang[SUP] 2 3 5 6 7 [/SUP], Xiao Wang[SUP] 9 10 11 [/SUP]
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) N[SUP]7[/SUP]-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.