Extracellular and membrane-targeted protein degradation (emTPD): Mechanisms, design frameworks, and therapeutic opportunities

Over the past five years, the field of extracellular and membrane-targeted protein degradation (emTPD) has reoriented target proteins toward endolysosomal degradation, providing an alternative to traditional inhibitors. Here, we classify current emTPD strategies according to the primary fate-determining module that commits cargo to degradation: (1) Receptor hijacking, in which endogenous receptors drive uptake and lysosomal routing; (2) Surface E3 ligase recruitment, in which ubiquitin serves as the internalization and sorting signal; (3) Receptor-independent or programmable routing mechanisms, which do not rely on canonical lysosomal shuttle receptors but instead encode degradative fate through alternative endocytic, sorting, or autophagy-linked cues. We synthesize shared mechanistic principles—membrane ternary-complex biophysics, endocytic flux, and condition-triggered dissociation—into a unified design framework that guides molecular engineering, tissue selectivity, and rational combination strategies. Major translational challenges include PK/PD modeling, tissue penetration, immunogenicity and safety window. With the emergence of early clinical evaluations (e.g., BHV-1400 entering early clinical evaluation), emTPD is gradually shifting towards clinical validation. In the future, the combination of artificial intelligence-driven design and pathway engineering will expand its therapeutic applications across tumors, autoimmune diseases, neurodegenerative disorders, and metabolic diseases.