Aptamer-Based Heterobifunctional Targeted Degraders in Disease Treatment.

Aptamers are short nucleic acid molecules that bind to targets with high specificity. Recognized as "chemical antibodies", they offer distinct advantages including strong programmability and ease of synthesis and chemical modification. Heterobifunctional targeted degraders were developed to address the challenges posed by traditionally "undruggable" targets and acquired drug resistance. The degraders recruit endogenous cellular degradation machinery to catalyze the removal of disease-associated proteins, thereby overcoming the limitations of conventional occupancy-driven inhibition. The fusion of aptamers with these degradation modalities has given rise to integrated platforms such as aptamer-proteolysis-targeting chimeras (PROTACs), aptamer-lysosome-targeting chimeras (LYTACs), and aptamer-autophagosome-tethering compounds (ATTECs). These conjugates combine the precise targeting ability of aptamers with the event-driven, catalytic nature of degradation technologies. As such, they not only expand the druggable target space to include intracellular proteins, membrane proteins, and pathogenic aggregates but also hold significant therapeutic potential in areas ranging from oncology and neurodegenerative disorders to infections and inflammatory diseases. Furthermore, degradation can be spatially and temporally controlled through receptor-mediated delivery or photo-switchable mechanisms. In this review, we provide a comprehensive summary of recent progress in studies on aptamer-based heterobifunctional degraders, with an emphasis on their design principles, biomedical applications, and therapeutic prospects.