Chemically modified mRNAs have great potential for therapeutic applications. The incorporation of base Z (2-aminoadenine) into mRNA creates Z-mRNA with improved translational capacity, decreased cytotoxicity, and reduced immunogenicity. Z-mRNA expands the scope of mRNA base modifications and offers a platform for mRNA-based therapeutics with minimal immunogenicity.
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 N-1-methylpseudouridine (m1 psi) 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 m1 psi-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.
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