PROTACs in personalized and precision medicine: transforming targeted therapy with advances in selectivity and patient stratification.

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative therapeutic strategy that extends beyond conventional occupancy-driven pharmacology by enabling the selective degradation of disease-causing proteins through the ubiquitin-proteasome system (UPS). Unlike traditional small-molecule inhibitors that transiently suppress protein function, PROTACs catalytically eliminate target proteins, thereby offering sustained pharmacological effects and the potential to bypass selected resistance mechanisms associated with conventional target inhibition, and expanding the druggable proteome to include previously undruggable targets. These unique properties position PROTACs as a promising platform for personalized and precision medicine. This review comprehensively examines recent advances in PROTAC technology with a particular emphasis on therapeutic selectivity, biomarker-guided patient stratification, and clinical translation. We discuss the structural design and mechanistic principles of PROTACs, including ternary complex formation, E3 ligase recruitment, ubiquitination, and proteasomal degradation. Recent innovations such as reversible covalent PROTACs, macrocyclic PROTACs, photo-switchable degraders (PHOTACs), conditional PROTACs, and the expanding repertoire of E3 ligases are highlighted for their potential to improve tissue specificity and therapeutic precision. Furthermore, the integration of computational modelling, artificial intelligence, molecular docking, molecular dynamics simulations, multi-omics technologies, CRISPR-based functional screening, and patient-derived organoids is discussed as a framework for rational degrader design and individualized therapeutic decision-making. The review also explores emerging applications of PROTACs in oncology, neurodegenerative disorders, autoimmune diseases, and infectious diseases while addressing current challenges related to pharmacokinetics, drug delivery, resistance mechanisms, biomarker validation, and regulatory considerations. Finally, we discuss emerging nanotechnology-enabled delivery strategies, companion-diagnostic concepts, and patient-specific degrader development as potential approaches to address pharmacokinetic, delivery, and translational barriers, while emphasizing that most of these strategies remain preclinical or investigational. Collectively, this review highlights the growing role of PROTACs as next-generation therapeutics capable of bridging chemical biology with precision medicine, supporting the development of potentially selective, biomarker-informed, and individualized treatment strategies.