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.
Yang et al. (2025) studied this question.