Lysosome-targeting chimeras enable targeted protein degradation

Bozhao Li; Yanyan Li; Jian Zhang; Siren Badama; Xian Zhao; Liping Wang; Tian Zhang; Xueting Wang; Xiaoqing Yi; Guo-Bin Ding; Xudong Wang; Guangjun Nie

doi:10.1016/j.chembiol.2026.01.008

Lysosome-targeting chimeras enable targeted protein degradation

Cell Chem Biol. 2026 Feb 18:S2451-9456(26)00028-0. doi: 10.1016/j.chembiol.2026.01.008. Online ahead of print.

Authors

Bozhao Li¹, Yanyan Li², Jian Zhang³, Siren Badama², Xian Zhao⁴, Liping Wang⁴, Tian Zhang², Xueting Wang⁵, Xiaoqing Yi⁶, Guo-Bin Ding⁷, Xudong Wang⁸, Guangjun Nie⁹

Affiliations

¹ Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot 010070, China; Institute of Nanotechnology and Intelligence (inAI), Jinan University, Guangzhou 510632, China. Electronic address: libz@imu.edu.cn.
² Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot 010070, China.
³ Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
⁴ National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Sinopharm Group, Beijing 101111, China.
⁵ Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China.
⁶ College of Pharmacy, Gannan Medical University, Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, Ganzhou 341000, China.
⁷ Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot 010070, China. Electronic address: ding@imu.edu.cn.
⁸ National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Sinopharm Group, Beijing 101111, China. Electronic address: wangxudong23@sinopharm.com.
⁹ CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China. Electronic address: niegj@nanoctr.cn.

PMID: 41713411
DOI: 10.1016/j.chembiol.2026.01.008

Abstract

Targeted protein degradation (TPD) has emerged as a powerful therapeutic paradigm by enabling the selective elimination of disease-associated proteins beyond the reach of conventional inhibition strategies. Among TPD approaches, lysosome-targeting chimeras (LYTACs) uniquely enable the degradation of extracellular and membrane-associated proteins through receptor-mediated endocytosis and lysosomal delivery. This Review provides a mechanistic and conceptual overview of LYTAC technology, emphasizing molecular classification based on ligand architecture, lysosome-targeting receptor engagement, and endocytic trafficking pathways. We discuss how receptors such as the cation-independent mannose-6-phosphate receptor and asialoglycoprotein receptor dictate internalization efficiency and degradation outcomes, and highlight key biochemical and cellular determinants governing target recognition, intracellular routing, and lysosomal processing. Finally, we examine major translational challenges, including tissue selectivity, pharmacokinetics, immunogenicity, and manufacturing constraints, and outline emerging design strategies such as ligand and linker engineering, modular scaffold optimization, and synthetic receptor recruitment that may enable next-generation LYTAC therapeutics with improved precision and clinical potential.

Keywords: LYTACs; extracellular protein degradation; lysosome-targeting chimeras; receptor-mediated endocytosis; targeted protein degradation.

Publication types

Review