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Study Finds N4-Acetylcytidine Matches Inflammation Control of N1-Methylpseudouridine While Increasing Protein Output in mRNA Tests
A Nature study finds ac4C-modified mRNA matches m1Ψ in reducing inflammation while producing more protein across cell and animal models. Slower elongation with the current standard contributed to lower output and more errors.
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N4-acetylcytidine produced higher protein levels than N1-methylpseudouridine in synthetic mRNA while matching its ability to limit inflammatory responses, according to research published in Nature. The study tested the modification across cultured cell lines, primary human monocyte-derived dendritic cells, and mouse liver.
In each system ac4C suppressed inflammation as effectively as m1Ψ, the current industry standard, yet drove greater protein output.
Single-molecule imaging showed similar ribosome densities on both types of transcripts. Translation elongation proceeded nearly twice as fast with ac4C-modified mRNA. The slower pace with m1Ψ reduced overall protein production and raised ribosome collisions that triggered quality-control pathways and +1 frameshifting.
Synthetic mRNAs are packaged in lipid nanoparticles and routinely incorporate modified ribonucleotides to increase stability, improve translation, and reduce immune detection. Recent work has linked m1Ψ to errors including premature termination and frameshifting. A related paper titled "N1-Methylpseudouridine directly modulates translation dynamics" appeared on 14 January 2026.
