RNA stability enhancers for durable base-modified mRNA therapeutics.

An element named A7 makes linear base-modified mRNA as stable as circular RNA while boosting translation, and in mouse liver sustains expression for over 2 weeks.

• Why it matters: Limited in vivo mRNA stability constrains vaccines and therapeutics, and more durable RNA formats can trade off translation, modification compatibility, and manufacturability.
• What they did: The team screened 196,277 viral sequences and found eleven elements that enhance mRNA stability and translation by recruiting TENT4 to extend the poly(A) tail and prevent deadenylation. Five elements, compatible with N1-methylpseudouridine, improved efficacy and reduced immunogenicity; A7 was tested across cell types, delivery methods, modifications, and coding sequences.
• The result: A7-containing linear mRNA produced substantially higher protein levels than circular RNA in mouse liver, with sustained expression lasting for over 2 weeks, enabling durable, low-immunogenic, simply manufactured linear mRNA platforms.

AI summary of the abstract · may contain errors · not medical advice · read the paper.