Applications of Lysosome‐Targeting Receptors (LTRs) in Targeted Protein Degradation

ABSTRACT Lysosome‐targeting chimeras (LYTACs) represent a novel class of targeted protein degradation (TPD) technologies that utilize lysosome‐targeting receptors (LTRs) to degrade extracellular and membrane‐bound proteins. Unlike traditional proteasomal degradation pathways, LYTACs direct target proteins to lysosomes for degradation through receptor‐mediated endocytosis, offering a promising solution for targeting previously “undruggable” extracellular proteins. To provide an in‐depth analysis of the current state of development, existing challenges, and promising future directions of LYTAC technologies, this review first introduces TPD strategies with a focus on LYTAC. It subsequently enumerates 15 LTRs employed in LYTAC systems, with detailed analysis of 9 representative LTRs and their corresponding targeted protein degradation chimera designs. Additionally, two transmembrane E3 ubiquitin ligases functioning as non‐classical LTRs are discussed. Finally, the review concludes by summarizing three major challenges currently facing LYTAC technologies, while presenting potential solutions supported by recent research advancements. This comprehensive analysis aims to provide emerging researchers in the LYTAC field with an updated overview of current developments, while offering valuable insights and research perspectives for scientists actively engaged in LYTAC‐related investigations.