Stable RNA elements open new possibilities for mRNA therapeutics

A research team led by Kim V. Narry has discovered compact viral RNA elements that can enhance mRNA stability and protein production. These elements could improve mRNA therapeutics for vaccines and other treatments. The study, published in Cell, also revealed a new mechanism where viruses recruit cellular enzymes to stabilize their RNA.

Messenger RNA (mRNA) carries genetic instructions for protein production, but its short lifespan limits its effectiveness. Viruses have evolved methods to protect their RNA, presenting potential solutions for mRNA stability. The researchers analyzed 337 vertebrate-infecting viruses and found hundreds of segments capable of boosting mRNA expression.

Many of these relied on a cellular enzyme called terminal nucleotidyltransferase 4 (TENT4), which extends the poly(A) tail of mRNA, slowing its degradation. The team identified 23 TENT4-dependent elements and named them tailons. Another potent element, Pt1, derived from Potamipivirus, directly recruits cellular enzymes to extend the poly(A) tail, functioning independently of TENT4.

Circular RNA, resistant to degradation, shows lower protein production efficiency than linear mRNA. However, adding tailons enhances linear mRNA stability, making it comparable to circular RNA. Linear mRNA with tailons achieved a protein half-life similar to circular RNA, remaining stable for up to two weeks in mice. This stability could reduce mRNA dosage, potentially lowering side effects.

The findings suggest tailons could improve mRNA therapeutics for various applications, including cancer and immune therapies.