The Delivery Strategies for PROTAC

Proteolysis-targeting chimeras (PROTACs) have revolutionized drug discovery by enabling event-driven degradation of previously "undruggable" proteins via the ubiquitin-proteasome system. Despite their catalytic mechanism and potential to overcome resistance, conventional PROTACs face critical translational bottlenecks: off-target protein degradation causing systemic toxicity, poor pharmacokinetics due to high molecular weight (700-1100 Da) and violation of Lipinski's rule of five, and insufficient tumor accumulation. To address these challenges, diverse delivery strategies have emerged. This chapter systematically examines three progressive tiers of PROTAC delivery: (i) molecular prodrug engineering using stimuli-activatable moieties (light, hypoxia, ROS, enzymes, X-ray, bioorthogonal chemistry), (ii) ligand-mediated active targeting (folate, aptamer, antibody), and (iii) nanoplatform-based systems (polymeric nanoparticles, microneedles, self-assembling nanofibers, biomimetic vesicles). We highlight how these strategies achieve spatiotemporally controlled, tumor-selective protein degradation while minimizing off-tumor toxicity. We also outline future directions including AI-assisted design, logic-gated multi-stimuli systems, oral formulation, and clinical translation. This chapter serves as a road map for developing next-generation intelligent PROTAC delivery systems for precision cancer therapy.