Advances in DNA-based proteolysis-targeting chimeras technology: Novel strategies for targeting previously undruggable proteins in cancer therapy

Targeted protein degradation (TPD) technology has emerged as a transformative therapeutic strategy for selectively eliminating aberrant proteins across diverse pathological conditions. This comprehensive review systematically examines recent advances in DNA-based proteolysis-targeting chimeras (DNA-PROTACs), which harness the exceptional specificity and binding affinity of DNA to substantially expand the targetable protein repertoire beyond conventional small molecule PROTACs. Through extensive literature analysis encompassing mechanistic studies, preclinical evaluations, and clinical investigations, we demonstrate that DNA-PROTACs effectively target previously undruggable proteins, including transcription factors, cell membrane proteins, and DNA damage response mediators. These innovative chimeric constructs exhibit superior catalytic efficiency through E3 ubiquitin ligase recruitment via the proteasomal degradation pathway, with unique advantages in linker optimization enabled by precise nucleotide-level control during DNA synthesis. Cell-based assays consistently reveal enhanced selectivity profiles and expanded therapeutic windows compared to traditional PROTAC modalities and alternative RNA-based approaches. Despite promising preclinical outcomes and advancing clinical development timelines, challenges in delivery optimization, molecular stability enhancement, and clinical translation persist. The integration of artificial intelligence-assisted drug design platforms and in vivo aptamer evolution technologies presents unprecedented opportunities for accelerating DNA-PROTACs development toward sub-nanomolar potency targets, positioning this technology as a paradigm-shifting approach in precision medicine across oncology, immunotherapy, and neurodegeneration therapeutics.