Hijacking Extracellular Targeted Protein Degrader-Drug Conjugates for Enhanced Drug Delivery.

ABSTRACT: Antibody-based therapeutics encompass diverse modalities for targeting tumor cells. Among these, antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. A major limitation of ADCs is their reliance on antigens with efficient internalization, while eTPD approaches, although capable of trafficking diverse targets to lysosomes, lack cytotoxic potency. To address this, we developed degrader-drug conjugates (DDCs), leveraging the endocytic and recycling activities of eTPD to enhance lysosomal delivery. We utilized fast internalizers, the low-density lipoprotein receptor (LDLR) and the chemokine receptor (CXCR7), to enhance lysosomal delivery. LDLR-based degraders enabled efficient and selective de

SUBMITTER: Zhao F 

PROVIDER: S-EPMC12576823 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature