Small-Molecule Ligands Targeting Lysosome-Shuttling Receptors and the Emerging Landscape of Lysosome-Targeting...

Lysosome-targeting chimeras (LYTACs) have expanded the scope of targeted protein degradation (TPD) by enabling the selective removal of extracellular proteins that are inaccessible to proteasome-dependent strategies. This Perspective examines small-molecule and peptide ligands that interact with several representative lysosome-shuttling receptors and analyzes their structural characteristics, binding mechanisms, and therapeutic implications. We also investigate emerging efforts to exploit noncanonical endocytic pathways mediated by lysosomal membrane proteins, glycosylphosphatidylinositol (GPI)-anchored receptors, lectin receptors, solute carriers, integrins, and GPCRs for LYTAC development. Compared with macromolecular conjugates, small-molecule LYTACs exhibit improved pharmacokinetics, tissue penetration, and synthetic accessibility. We propose a mechanistically informed framework for the rational design of next-generation LYTACs, emphasizing the importance of ligand engineering and receptor selection. Finally, we critically discuss key challenges and future opportunities to optimize the specificity, efficacy, and translational potential of LYTACs.