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As you are well aware, N¹-methylpseudouridine (m¹Ψ) has long served as the "gold standard" for mRNA modification in vaccine development. However, recent studies published in Nature and Nature Reviews Drug Discovery (N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity https://www.nature.com/articles/s41586-026-10729-8) have revealed significant limitations of m¹Ψ, including ribosomal elongation slowdown and high-frequency +1 frameshift mutations, which constrain its applicability in protein replacement therapy, in vivo CAR/TCE expression, and gene editing delivery.
In contrast, the natural modification N⁴-acetylcytidine (ac⁴C) has emerged as a transformative alternative:
1. Comparable immunogenicity to m¹Ψ — ideal safety profile
2. Up to 3.5× higher protein expression — demonstrated in liver-targeted LNP experiments compared to m¹Ψ
3. Near-elimination of frameshift errors — markedly improved translational fidelity
4. No ribosomal congestion or RQC degradation — maintains smooth, rapid translation through strengthened C-G base pairing.
Chemical Structure:
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