Molecular design and delivery of extracellular and membrane protein degradation chimeras.

Abstract

Extracellular and membrane-associated proteins constitute a substantial therapeutic target space that remains largely inaccessible to intracellular degradation strategies based on the ubiquitin-proteasome system. Membrane and extracellular targeted protein degradation (meTPD) addresses this limitation by coupling target recognition to degradation-competent uptake and intracellular sorting rather than relying on a single receptor or platform. In this Review, we organize meTPD strategies according to their trafficking and degradation routes, including lysosome-targeting receptor-dependent systems, transmembrane E3 ligase recruitment, receptor-independent internalization, lysosomal-sorting sequences and autophagy-mediated clearance. We then examine how ligand affinity and epitope accessibility, ternary-complex geometry, linker architecture, covalency, valency, receptor recycling and degrader reuse collectively determine productive degradation. Particular attention is given to spatial selectivity across tissues, cell populations and subcellular organelles, as well as to artificial intelligence-assisted design, stimuli-responsive activation and delivery systems that regulate the exposure and trafficking of meTPDs. Finally, we discuss emerging clinical evidence, convergence with antibody-drug conjugate-derived modalities, the hook effect and plausible resistance mechanisms. By integrating molecular design, receptor biology, intracellular trafficking, delivery and pharmacodynamic considerations, this Review provides a framework for selecting disease-matched degradation routes and advancing meTPDs from platform-specific demonstrations towards predictable therapeutic modalities.