Strategies for targeted protein degradation through lysosomal pathways

While proteolysis-targeting chimeras (PROTACs) represent a breakthrough in targeted protein degradation (TPD), their applicability is restricted by fundamental limitations. Mechanistically, they are mainly limited to proteins with accessible cytosolic domains for ligand binding and ternary complex formation. Physically, the proteasome's narrow pore diameter largely bars folded, oligomeric, or aggregated protein species from entering. These inherent restrictions collectively exclude a broad range of challenging targets, including many membrane and extracellular proteins lacking suitable cytosolic ligands, as well as insoluble aggregates and dysfunctional organelles. Encouragingly, the lysosome offers a versatile alternative pathway, capable of degrading a wide spectrum of macromolecules and cellular structures. Lysosome-engaging TPD strategies have recently gained significant traction, offering the potential to diversify the TPD toolkit, overcome the limitations of PROTACs, and expand the target scope of TPD technologies to encompass a broader range of human diseases. This review aims to comprehensively survey this rapidly advancing field by examining the design principles, demonstrating its potential through case studies, and critically evaluating future opportunities and challenges.