Abstract / Summary
ABSTRACT Extracellular targeted protein degradation (eTPD) systems typically utilize lysosome‐targeting receptors (LTRs) to redirect extracellular and membrane proteins for lysosomal degradation. Expanding the repertoire of clinically relevant LTRs could broaden the therapeutic potential of eTPD. Here we report trophoblast cell surface antigen‐2 (TROP2), a clinically validated tumor‐associated antigen targeted by approved antibody‐drug conjugates, as a promising LTR for tumor cell‐selective eTPD. We develop TROP2‐targeting chimeras (TRTACs) by fusing a TROP2‐binding nanobody to target‐specific nanobodies. This fully genetically encoded, ∼30 kDa nanobody format enables modular construction, broad target adaptability, and favorable tumor penetration. TRTACs induce degradation of diverse membrane proteins, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and programmed death‐ligand 1 (PD‐L1), preferentially in tumor cells rather than in nonmalignant cells. We further designed TRTAC‐drug conjugates (TRTAC‐DCs) by attaching cytotoxic payloads to TRTACs, enabling enhanced drug delivery together with protein degradation. The HER2‐targeted TRTAC‐DC reduced SKBR3 cell viability by 50% at 0.2 nM and showed potent antitumor activity in vivo, without significant body weight loss or histological abnormalities in major organs. These findings establish TROP2 as a clinically relevant LTR and provide a modular platform that combines tumor cell‐selective extracellular protein degradation with enhanced payload delivery.