Abstract

Endocytosis and lysosomal degradation are critical pathways that determine the intracellular trafficking and therapeutic efficacy of antibody-drug conjugates (ADCs). However, inefficient internalization and lysosomal trafficking often limit ADC potency. Here, we introduce receptor-ubiquitination-targeting ADCs (ubitaADCs), a class of ADCs engineered to simultaneously bind target receptors and E3 ubiquitin ligases, thereby inducing receptor ubiquitination to enhance endocytosis and lysosomal delivery. Using engineered ubitaADC targeting epidermal growth factor receptor (EGFR), we demonstrate that promoting receptor ubiquitination accelerates internalization and lysosomal trafficking, leading to enhanced intracellular drug release and improved tumor cell killing. Mechanistic studies reveal that E3 ligase recruitment facilitates receptor ubiquitination, triggering endocytosis and subsequent lysosomal degradation. In vivo , ubitaADCs exhibit superior antitumor efficacy compared to conventional ADCs. This study establishes receptor ubiquitination as a powerful strategy to optimize ADC function and provides a generalizable approach for improving targeted protein degradation in therapeutic applications.