Sub-stoichiometric 5-methoxyuridine modification enables tunable immune evasion and protein expression from synthetic mRNAs

Jonathan R. Miles; Sarah Masterson; Eleanor Bellows; Fabio Fisher; Ritu Rani; Sara Marelli; Colin Hardman; Luigi Grassi; L. Santos; Victoria James; Nigel P. Mongan; Christopher J. Hayes; Matthew Loose; Janet M. Daly; J A Button; George Thom; Rupert G. Fray; Nathan Archer

doi:10.1016/j.omtn.2026.103058

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Abstract

, where lipid nanoparticle-delivered mRNA encoding human IgG produced approximately 2-fold higher serum levels with 50% 5moU than with 100% m1Ψ. Transcriptomic profiling revealed reduced interferon-stimulated gene induction following delivery of 5moU-modified mRNA compared with unmodified and m1Ψ modified mRNA. Unlike m1Ψ, 5moU modification consistently suppressed innate responses to double-stranded RNA. Together, these data demonstrate that partial nucleotide substitution can outperform current mRNA modification strategies and expand the design space for therapeutic mRNAs.

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Miles et al. (2026) studied this question.

synapsesocial.com/papers/6aa6e46322b0548423397a27 https://doi.org/10.1016/j.omtn.2026.103058

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Sub-stoichiometric 5-methoxyuridine modification enables tunable immune evasion and protein expression from synthetic mRNAs

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Sub-stoichiometric 5-methoxyuridine modification enables tunable immune evasion and protein expression from synthetic mRNAs

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