Reversible Control of RNA Splicing by Photoswitchable Small Molecules

Dynamics are intrinsic to both RNA function and structure.Yet,the available means to precisely provide RNA-based processes withspatiotemporal resolution are scarce. Here, our work pioneers a reversibleapproach to regulate RNA splicing within primary patient-derived cellsby synthetic photoswitches. Our small molecule enables conditionalreal-time control at mRNA and protein levels. NMR experiments, togetherwith theoretical calculations, photochemical characterization, fluorescencepolarization measurements, and living cell-based assays, confirmedlight-dependent exon inclusion as well as an increase in the targetfunctional protein. Therefore, we first demonstrated the potentialof photopharmacology modulation in splicing, tweaking the currentoptochemical toolkit. The timeliness on the consolidation of RNA researchas the driving force toward therapeutical innovation holds the promisethat our approach will contribute to redrawing the vision of RNA.