Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons
Abstract Although messenger RNA (mRNA) vaccines have been employed to prevent the spread of COVID-19, they are still limited by instability and low translation capacity. Alterations in tRNA abundance and modification, linking codon optimality, impact mRNA stability and protein output in a codon-depe...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62981-7 |
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| _version_ | 1849226070366093312 |
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| author | Liangzhen Dong Jiayu Wang Qing Xia |
| author_facet | Liangzhen Dong Jiayu Wang Qing Xia |
| author_sort | Liangzhen Dong |
| collection | DOAJ |
| description | Abstract Although messenger RNA (mRNA) vaccines have been employed to prevent the spread of COVID-19, they are still limited by instability and low translation capacity. Alterations in tRNA abundance and modification, linking codon optimality, impact mRNA stability and protein output in a codon-dependent manner, suggesting tRNA as a potential translation enhancer. Here, we report a strategy named tRNA-plus to augment translation via artificially modulating tRNA availability. Overexpression of specific tRNAs enhances the stability and translation efficiency of SARS-CoV-2 Spike mRNA, boosting protein levels up to 4.7-fold. Additionally, chemically synthesized tRNAs bearing multiple site-specific modifications, particularly at the anticodon-loop and TΨC-loop, exhibit on average ~4-fold higher decoding efficacy than unmodified tRNAs, along with increased stability and reduced immunotoxicity. Furthermore, codelivery of Spike mRNA vaccine and tRNA through lipid nanoparticles elicits augmented humoral and cellular immune responses in vivo. These results presented here provide a general approach to elevate mRNA translation potency, with applications in diverse translation-based fields. |
| format | Article |
| id | doaj-art-77770dcdcdfa400a9edef42cc4ca8389 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-77770dcdcdfa400a9edef42cc4ca83892025-08-24T11:39:42ZengNature PortfolioNature Communications2041-17232025-08-0116111810.1038/s41467-025-62981-7Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codonsLiangzhen Dong0Jiayu Wang1Qing Xia2State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityAbstract Although messenger RNA (mRNA) vaccines have been employed to prevent the spread of COVID-19, they are still limited by instability and low translation capacity. Alterations in tRNA abundance and modification, linking codon optimality, impact mRNA stability and protein output in a codon-dependent manner, suggesting tRNA as a potential translation enhancer. Here, we report a strategy named tRNA-plus to augment translation via artificially modulating tRNA availability. Overexpression of specific tRNAs enhances the stability and translation efficiency of SARS-CoV-2 Spike mRNA, boosting protein levels up to 4.7-fold. Additionally, chemically synthesized tRNAs bearing multiple site-specific modifications, particularly at the anticodon-loop and TΨC-loop, exhibit on average ~4-fold higher decoding efficacy than unmodified tRNAs, along with increased stability and reduced immunotoxicity. Furthermore, codelivery of Spike mRNA vaccine and tRNA through lipid nanoparticles elicits augmented humoral and cellular immune responses in vivo. These results presented here provide a general approach to elevate mRNA translation potency, with applications in diverse translation-based fields.https://doi.org/10.1038/s41467-025-62981-7 |
| spellingShingle | Liangzhen Dong Jiayu Wang Qing Xia Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons Nature Communications |
| title | Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons |
| title_full | Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons |
| title_fullStr | Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons |
| title_full_unstemmed | Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons |
| title_short | Chemically modified tRNA enhances the translation capacity of mRNA rich in cognate codons |
| title_sort | chemically modified trna enhances the translation capacity of mrna rich in cognate codons |
| url | https://doi.org/10.1038/s41467-025-62981-7 |
| work_keys_str_mv | AT liangzhendong chemicallymodifiedtrnaenhancesthetranslationcapacityofmrnarichincognatecodons AT jiayuwang chemicallymodifiedtrnaenhancesthetranslationcapacityofmrnarichincognatecodons AT qingxia chemicallymodifiedtrnaenhancesthetranslationcapacityofmrnarichincognatecodons |