In vivo fate-guided design of efficient delivery systems for PROTACs: from molecular rationales to clinical progress

Despite two decades of intensive molecular engineering, the clinical translation of proteolysis-targeting chimeras (PROTACs) remains constrained by a fundamental paradox: high in vitro potency often fails to translate into in vivo efficacy due to poor pharmacokinetics (PK)/pharmacodynamics (PD) profiles and uncontrolled biodistribution. This review departs from conventional narratives centered on potency by introducing a framework focused on drug fate that explicitly connects the absorption, distribution, metabolism, excretion (ADME), and tumor targeting of PROTACs with the rational design of advanced delivery systems. We first dissect the primary physiological barriers that undermine PROTAC performance in vivo, including rapid clearance, suboptimal tissue penetration, and off-target accumulation. Furthermore, we argue that efficient delivery must be engineered from the ground up based on how PROTACs behave inside the body. To this end, we systematically evaluate three tiers of delivery platforms, comprising small molecule prodrugs, macromolecular carriers, and systems based on nanoparticles, with particular emphasis on how each platform can be optimized to overcome specific PK/PD bottlenecks. Crucially, we propose a performance-by-design roadmap that integrates molecular-level innovations with nanoscale delivery engineering, shifting the field's focus from in vitro degradation potency toward predictable in vivo outcomes. By providing rational design principles grounded in the real-world fate of PROTACs, this review offers a timely paradigm shift that aims to accelerate clinical candidate development and unlock the full therapeutic potential of targeted protein degradation (TPD) in cancer.