Nature biotechnologyNov 7, 2025

RNA stabilizers for long-lasting modified mRNA medicines

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Viral RNA stability enhancers may make base-modified linear mRNA longer lasting while preserving strong translation.

Evidence

A formulation/platform experiment screened 196,277 viral sequences and tested selected enhancers across cells and mouse liver, where A7-containing linear mRNA produced higher protein than circular RNA with expression lasting over 2 weeks.

Caveat

The evidence is preclinical platform work, so durability, immunogenicity, and manufacturing advantages are not yet shown in humans.

Simplified

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 N-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. 1