ArticleMolecular therapy. Nucleic acids2026
Codon-dependent translation of N1-ethylpseudouridine-modified mRNA reduces innate immunity while preserving vaccine immunogenicity.
Article in Molecular therapy. Nucleic acids, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Messenger RNA (mRNA) vaccines are a versatile platform for rapid vaccine development; however, nucleoside modifications must be optimized to balance translational efficiency and innate immune activation. Here, we evaluated N1-ethylpseudouridine (Et1Ψ) as an alternative to the widely used N1-methylpseudouridine (m1Ψ). Et1Ψ-modified mRNA exhibited a distinct codon-dependent translational sensitivity, with increased UUU codon content leading to reduced protein expression. Importantly, synonymous codon optimization that eliminated UUU codons restored translation efficiency to levels comparable to those of m1Ψ-modified mRNA across multiple cell types. Despite this constraint, Et1Ψ consistently reduced innate immune activation
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