Lysosome-Targeting Chimeras (LYTACs): From Modular Design Principles to Diverse Therapeutic Applications

Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy, but most existing approaches are restricted to intracellular proteins. Lysosome-targeting chimeras (LYTACs) expand the scope of TPD by enabling the selective degradation of extracellular and membrane-associated proteins through the endosomal-lysosomal pathway. This review provides a comprehensive overview of LYTAC technology, focusing on its molecular architecture and mechanism of action. We systematically examine the evolution of LYTACs from two key design dimensions: (1) the diversity of protein-of-interest (POI) binders, including antibodies, aptamers, small molecules, peptides, and DNA scaffolds; and (2) the expanding repertoire of lysosomal targeting receptors (LTRs), from classical receptors, cation-independent mannose-6-phosphate receptor (CI-M6PR) and asialoglycoprotein receptor (ASGPR), to emerging tissue-restricted, multifunctional, and programmable entry routes. Finally, we discuss strategies to enhance degradation efficiency, pharmacokinetics/pharmacodynamics (PK/PD) profiles, and address key challenges for clinical translation, offering a framework for the rational design of next-generation LYTAC therapeutics.