Unlocking the “undruggable”: current landscape and emerging frontiers in lysosomal receptor-mediated protein degradation

Extracellular and membrane-associated proteins are essential in signal transmission, immunological control, and disease pathogenesis; nonetheless, their 'undruggable' characteristics have historically impeded drug discovery. The targeted protein degradation (TPD) technologies provide innovative solutions to address this dilemma. Despite the rapid advancement of techniques such as Proteolysis-targeting chimera (PROTACs) that utilize the Ubiquitin-proteasome system (UPS), their applicability is limited to intracellular proteins. Lysosome-targeting chimeras (LYTACs), utilizing the endocytosis-lysosomal route, facilitate the selective degradation of secreted and transmembrane proteins, thereby considerably broadening the target spectrum of TPD. Since its inception in 2020, the LYTAC platform has consistently progressed, incorporating several Lysosome-targeting receptor (LTR) targeting techniques and innovative delivery vehicles, including aptamers, peptides, and nanoparticles. It has exhibited promise in oncology, neurological conditions, and immune-mediated disorders. Nevertheless, LYTAC encounters several obstacles, such as intricate ligand design, potential immunogenicity, inadequate tissue selectivity, and restricted clinical validation. Platforms and tactics designed to improve degrading efficiency, broaden disease applicability, and facilitate clinical translation signify interesting research avenues in this domain. This paper presents a thorough evaluation of the research advancements and application potential of LYTAC technology, while examining significant limitations and future direction of development.