Lysosome‐Mediated Targeted Protein Degradation: Emerging Chimeric Platforms for Extracellular and Intracellular Therapeutics

Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease‐associated proteins. While proteolysis‐targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin–proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane‐bound. Lysosome‐targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine‐targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome‐mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far‐reaching applications in precision medicine and chemical biology.