Small-molecule-mediated RNA targeting: emerging strategies and therapeutic potential of RiboTAC

Many disease-associated proteins are difficult to target using conventional small molecules or biologics. RNA offers a promising therapeutic strategy because its structural motifs can create recognition sites for regulatory proteins and small molecules, enabling intervention upstream of proteins that are otherwise considered "undruggable". Recent advances in RNA-targeting therapeutics, particularly RNA-binding small molecules, have demonstrated the feasibility of selectively modulating RNA maturation, splicing, translation, and degradation. However, their broader clinical application is still limited by non-specific toxicity, off-target effects, stability concerns, and delivery challenges. Targeted protein degradation is a remarkable therapeutic modality that has been widely used to target undruggable pathogenic proteins. In relation to this, a currently emerging research field is that of ribonuclease-targeting chimeras (RiboTACs). Unlike the "occupancy-based" mode of small-molecule inhibitors (SMIs), RiboTACs recruit endogenous ribonucleases to selectively degrade disease-associated RNA transcripts through an event-driven mechanism, which enables efficient removal of pathogenic RNAs while offering advantages with regard to medicinal chemistry optimization compared with oligonucleotide-based approaches. In this perspective, we systematically summarize the classification of targetable RNAs, recent advances in RNA-targeting small molecules, and the design principles, applications, and future challenges of RiboTACs.