Nucleic acid-based PROTACs: emerging strategies and future perspectives

Targeted protein degradation (TPD) technology achieves selective degradation of target proteins through the ubiquitin-proteasome system (UPS) or lysosomal pathways. Among TPD strategies, proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach in innovative drug discovery, offering unique advantages such as the ability to target "undruggable" proteins, catalytic degradation kinetics, potential to circumvent drug resistance, and high selectivity. However, conventional small-molecule PROTACs depend on ligands binding to target proteins, limiting their effectiveness against molecules without well-defined binding sites, such as transcription factors (TFs) and RNA-binding proteins (RBPs). To overcome this limitation, oligonucleotide-based PROTAC technology has been developed, utilizing sequence-specific nucleic acid recognition to significantly expand the repertoire of degradable targets. This review systematically summarizes recent advances in oligonucleotide-PROTACs, including innovative designs like TF-PROTACs, RNA-PROTACs, G4-PROTACs, and aptamer-PROTACs, along with their therapeutic potentials. We further discuss persisting challenges such as molecular stability and delivery efficiency, and propose future directions for the field. By integrating nucleic acid molecular biology with protein degradation technologies, this interdisciplinary paradigm promises to unlock novel therapeutic strategies for "undruggable" targets and previously intractable diseases.