The limited stability of mRNA in vivo remains a major challenge for vaccines and therapeutics. While alternative RNA formats such as circular RNA or self-amplifying RNA offer greater durability, these modalities often suffer from low translation, modification incompatibility and difficult manufacturing. To overcome these limitations, we screen 196,277 viral sequences and identify eleven elements that strongly enhance mRNA stability and translation. Mechanistically, they recruit TENT4 to extend the poly(A) tail, preventing deadenylation. Five of them are compatible with N1-methylpseudouridine, which improves mRNA efficacy and reduces immunogenicity. An element named A7 demonstrates particularly robust performance across cell types, delivery methods, modifications and coding sequences, making linear mRNA as stable as circular RNA while achieving higher translation efficiency. In mouse liver, A7-containing linear mRNA exhibits substantially higher protein levels than circular RNA, with sustained expression lasting for over 2 weeks. These RNA stability enhancers enable robust linear mRNA platforms that combine high and durable expression, low immunogenicity and simple manufacturing.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.