ACS synthetic biologyFeb 18, 2026

Adding a human CU-rich sequence to synthetic mRNA improves its stability and expression in living organisms

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A 40-nt human ARF6 3' UTR element may make synthetic mRNA more stable and productive.

Evidence

Cell transfection and mouse LNP platform experiments showed ARF6.40 increased EGFP mRNA half-life and protein levels and produced higher, more sustained RBD secretion or luciferase expression.

Caveat

The evidence is preclinical and construct-specific, with no human therapeutic efficacy or safety data.

Simplified

Synthetic mRNA provides a powerful platform to transfer genetic information encoding therapeutic proteins in vivo. However, their applications are limited by their intrinsic instability and insufficient protein yield. Here we report a 40-nt RNA sequence (ARF6.40) that markedly improves mRNA stability and protein bioavailability of synthetic mRNA. ARF6.40, identified from the 3' UTR of the human ARF6 mRNA, contains a novel CU-rich element that interacts with the protein U2AF2. Compared with the broadly used globin 3' UTR, fusing ARF6.40 to the 3' UTR of EGFP mRNA results in markedly increased mRNA half-life and protein level; transfection of cells with SARS-CoV-2 RBD-encoding mRNA or administration of mice with LNP-encapsulated firefly luciferase mRNA fused with ARF6.40 leads to significantly higher and more sustained RBD secretion or luciferase expression in vivo. Together, our study demonstrates the potential of ARF6.40 in mRNA therapeutics and provides new insights into how the expression of ARF6 is regulated.