Lysosome-targeting chimeras enable targeted protein degradation

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.