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Most eTPD platforms employ heterobifunctional chimeras that link proteins of interest (POIs) to specific endocytic effectors (EEs), either lysosome\u2010targeting receptors (LTRs) or membrane\u2010bound 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\u2010independent mannose\u20106\u2010phosphate receptor (CI\u2010M6PR) 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\u2010surface E3 ligase\u2010based degraders and emerging EE\u2010independent strategies\u2014receptor\u2010independent membrane\u2010interacting modalities exemplified by cell\u2010penetrating peptides\u2014that 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.<\/jats:p>","DOI":"10.1002\/med.70112","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:15:13Z","timestamp":1792566913000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Landscape of Endocytic Effectors for Extracellular Targeted Protein Degradation"],"prefix":"10.1002","author":[{"given":"Yuxin","family":"Liang","sequence":"first","affiliation":[{"name":"General Surgery, Cancer Center, Department of Hepatobiliary &amp; Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital Hangzhou Medical College Hangzhou Zhejiang China"},{"name":"Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and 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