Small-Molecule Activation of mRNA Translation by Click-to-Release Reaction in Cells

T. Vosman, F. Burba, M. Sumser, M. Vrabel, H. Mikula, A. Rentmeister

Angew. Chem. Int. Ed. 2026, 65, e24223
DOI: 10.1002/anie.202524223

A new method to control mRNA activity using bioorthogonal click-to-release reactions is presented. The 5′ cap is modified with a trans-cyclooctene (TCO) that quickly reacts with hydroxyaryl-tetrazines and efficiently releases the native cap 0. TCO-capped mRNAs are initially translationally inactive but can be activated with non-toxic, cell-permeable tetrazines. This strategy offers a versatile way to regulate mRNA translation in eukaryotic cells.