Landscape of Endocytic Effectors for Extracellular Targeted Protein Degradation.

Extracellular targeted protein degradation (eTPD) has emerged as a new strategy for regulating the abundance and activity of extracellular and membrane proteins, with prominent potential to address traditionally undruggable targets in oncology, autoimmune diseases, and neurodegenerative disorders. Most eTPD platforms employ heterobifunctional chimeras that link proteins of interest (POIs) to specific endocytic effectors (EEs), either lysosome-targeting receptors (LTRs) or membrane-bound E3 ubiquitin ligases, to direct POIs to lysosomes for degradation. Since EE engagement dictates cellular uptake, intracellular trafficking route, recycling kinetics, tissue specificity, and overall degradation efficacy, one compelling topic in the eTPD community is to identify effective EEs for developing new eTPD tools. To inform new EE discovery, here we review the current landscape of EEs utilized in eTPD. We categorize LTRs based on their ligand specificity and discuss representative receptors including the cation-independent mannose-6-phosphate receptor (CI-M6PR) and the asialoglycoprotein receptor (ASGPR), with emphasis on their internalization and trafficking characteristics. For each category, we highlight representative degrader designs and assess how degrader attributes such as ligand format, valency, molecular size, linker chemistry, and linker length influence trafficking properties and degradation efficacy. We further discuss cell-surface E3 ligase-based degraders and emerging EE-independent strategies-receptor-independent membrane-interacting modalities exemplified by cell-penetrating peptides-that exploit alternative endocytic pathways without relying on specific effector expression. Finally, we discuss key challenges and future opportunities for integrating effector biology with degrader engineering to advance eTPD toward therapeutic drug discovery.