Improving Proteolysis‐Targeting Chimera Delivery by Targeting Key Biomarkers in Tumor Endocytosis Pathways

ABSTRACT

Proteolysis‐targeting chimeras (PROTACs) are promising therapeutic agents for targeted protein degradation via the ubiquitin‐proteasome system; however, their clinical application is severely constrained by poor membrane permeability due to high molecular weight and polar surface area, limiting passive diffusion. Emerging evidence suggests that receptor‐mediated endocytosis within tumor microenvironments provides an alternative and potentially generalizable entry route for PROTAC delivery independent of classical diffusion. This review proposes a systematic framework for tumor endocytosis‐guided PROTAC delivery, centered on the identification and exploitation of endocytic biomarkers. A three‐tiered screening strategy is established based on tumor‐selective expression, validated internalization capacity, and functional relevance to tumor dependency. Using this framework, nine representative biomarkers are evaluated with respect to endocytic pathways, intracellular trafficking fate, and delivery suitability. Furthermore, we present a unified PROTAC engineering strategy matrix integrating ligand design, cleavable linker chemistry, and endosomal escape modules to align with receptor‐specific trafficking behaviors. A multiscale validation pipeline covering binding, internalization, intracellular release, and in vivo pharmacodynamics is also outlined. Collectively, this review establishes tumor endocytic pathways as programmable delivery interfaces, providing a rational roadmap for next‐generation PROTAC design with improved efficiency and translational potential.