Hydrogen peroxide-triggered gene silencing in mammalian cells through boronated antisense oligonucleotides

Abstract

Hydrogen peroxide (H₂O₂) is a reactive oxygen species (ROS) involved in various diseases, including neurodegeneration, diabetes, and cancer. Here, we introduce a new approach to use H₂O₂ to modulate specific gene expression in mammalian cells. H₂O₂-responsive nucleoside analogues, in which the Watson–Crick faces of the nucleobases are caged by arylboronate moieties, were synthesized. One of these analogues, boronated thymidine (dT^B), was incorporated into oligodeoxynucleotides (ODNs) using an automated DNA synthesizer. The hybridization ability of this boronated ODN to complementary RNA was clearly switched in the off-to-on direction upon H₂O₂ addition. Furthermore, we demonstrated H₂O₂-triggered gene silencing in mammalian cells using antisense oligonucleotides (ASOs) modified with dT^B. Our approach can be used for the regulation of any gene of interest by the sequence design of boronated ASOs and will contribute to the development of targeted disease therapeutics.