Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells
Summary: Chemically modified mRNAs hold great potential for therapeutic applications in vivo. Currently, the base modification scheme largely preserves the canonical Watson-Crick base pairing, thus missing one mode of mRNA modulation by altering its secondary structure. Here we report the incorporat...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223018163 |
| _version_ | 1797647864049958912 |
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| author | Meng Zhang Nilmani Singh Mary Elisabeth Ehmann Lining Zheng Huimin Zhao |
| author_facet | Meng Zhang Nilmani Singh Mary Elisabeth Ehmann Lining Zheng Huimin Zhao |
| author_sort | Meng Zhang |
| collection | DOAJ |
| description | Summary: Chemically modified mRNAs hold great potential for therapeutic applications in vivo. Currently, the base modification scheme largely preserves the canonical Watson-Crick base pairing, thus missing one mode of mRNA modulation by altering its secondary structure. Here we report the incorporation of base Z (2-aminoadenine) into mRNA to create Z-mRNA with improved translational capacity, decreased cytotoxicity, and drastically reduced immunogenicity compared to the unmodified mRNA in mammalian cells. In particular, the A-to-Z substitution renders modified mRNAs less immunogenic than the state-of-the-art base modification N1-methylpseudouridine (m1ψ) in mouse embryonic fibroblast cells. As a proof of concept, we developed a Z-mRNA-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antigen-encoding Z-mRNA elicited substantial humoral and cellular immune responses in vivo in mice, albeit with relatively lower efficacy than the state-of-the-art m1ψ-mRNA. Z-mRNA expands the scope of mRNA base modifications toward noncanonical bases and could offer an advantageous platform for mRNA-based therapeutics where minimal immunogenicity is desired. |
| first_indexed | 2024-03-11T15:22:45Z |
| format | Article |
| id | doaj.art-019d4e9895244cc89affbf65252a6ad2 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T15:22:45Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-019d4e9895244cc89affbf65252a6ad22023-10-28T05:08:15ZengElsevieriScience2589-00422023-10-012610107739Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cellsMeng Zhang0Nilmani Singh1Mary Elisabeth Ehmann2Lining Zheng3Huimin Zhao4Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USACarl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USADepartment of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USADepartment of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USADepartment of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Corresponding authorSummary: Chemically modified mRNAs hold great potential for therapeutic applications in vivo. Currently, the base modification scheme largely preserves the canonical Watson-Crick base pairing, thus missing one mode of mRNA modulation by altering its secondary structure. Here we report the incorporation of base Z (2-aminoadenine) into mRNA to create Z-mRNA with improved translational capacity, decreased cytotoxicity, and drastically reduced immunogenicity compared to the unmodified mRNA in mammalian cells. In particular, the A-to-Z substitution renders modified mRNAs less immunogenic than the state-of-the-art base modification N1-methylpseudouridine (m1ψ) in mouse embryonic fibroblast cells. As a proof of concept, we developed a Z-mRNA-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antigen-encoding Z-mRNA elicited substantial humoral and cellular immune responses in vivo in mice, albeit with relatively lower efficacy than the state-of-the-art m1ψ-mRNA. Z-mRNA expands the scope of mRNA base modifications toward noncanonical bases and could offer an advantageous platform for mRNA-based therapeutics where minimal immunogenicity is desired.http://www.sciencedirect.com/science/article/pii/S2589004223018163Biological sciencesBiochemistryMedical biochemistry |
| spellingShingle | Meng Zhang Nilmani Singh Mary Elisabeth Ehmann Lining Zheng Huimin Zhao Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells iScience Biological sciences Biochemistry Medical biochemistry |
| title | Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells |
| title_full | Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells |
| title_fullStr | Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells |
| title_full_unstemmed | Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells |
| title_short | Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells |
| title_sort | incorporation of noncanonical base z yields modified mrna with minimal immunogenicity and improved translational capacity in mammalian cells |
| topic | Biological sciences Biochemistry Medical biochemistry |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223018163 |
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