Nectin4-targeted molecular imaging for precise endoscopic diagnosis and image-guided surgery in bladder cancer.

Bladder cancer (BC) is a common malignancy, yet conventional white light cystoscopy (WLC) has suboptimal diagnostic accuracy. Nectin4, a membrane protein highly expressed in BC, is an attractive molecular imaging target. By conjugating indocyanine green (ICG) to enfortumab vedotin, we develop NECTIN4-ICG, a BC-specific fluorescence imaging probe. In BC mouse models, NECTIN4-ICG enables targeted detection and doubles the complete tumor resection rate. In an ex vivo study of 18 fresh human bladders yielding 82 specimens, NECTIN4-ICG-guided biopsy achieves 96.3% diagnostic accuracy. In a clinical trial involving 20 patients yielding 198 specimens, NECTIN4-ICG-guided biopsy achieves 96.0% diagnostic accuracy and 91.1% tumor margin detection, outperforming WLC (82.2% and 73.3%). NECTIN4-ICG also enables fluorescence-guided TURBT, enhancing real-time visualization, margin assessment, and carcinoma in situ detection with a favorable safety profile. This clinical trial is registered under ChiCTR2200067094 and ChiCTR2400092677.