Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing

Abstract

ABSTRACT Lysosome‐targeting chimeras (LYTACs) have emerged as a strategy for eliminating secreted, extracellular, and plasma‐membrane proteins by redirecting them to the endolysosomal system. By coupling target recognition to receptor‐mediated uptake, LYTACs exploit endogenous trafficking pathways to access disease‐associated proteins beyond the reach of conventional intracellular degradation mechanisms. Related target‐intrinsic and cross‐linking‐driven strategies can likewise promote lysosomal target delivery without recruiting a separate clearance receptor. However, target internalization alone does not establish productive degradation. Following entry, target‐containing complexes encounter a competitive endosomal network in which they may recycle, undergo retrograde transport or transcytosis, remain in non‐degradative compartments, or proceed to lysosomes. Here, we present a routing‐centered framework for understanding and designing extracellular and membrane‐protein degradation. We discuss how target biology, receptor choice, tissue distribution, ligand competition, signaling liability, molecular architecture, and intracellular sorting shape degrader performance. We also outline evidence standards for distinguishing bona fide lysosome‐dependent target loss from surface depletion, redistribution, epitope masking, shedding, secretion blockade, transcriptional effects, and nonspecific toxicity. Together, these principles define the transition from receptor hijacking to programmable endolysosomal routing.