A Hypoxia-Activated Photomolecular Glue with Synergistic Cyclin K Degradation and Phototherapy for Cancer Treatment.

Cyclin K is overexpressed in multiple tumors and plays critical roles in tumorigenesis, making it a promising therapeutic target. Although the antitumor potential of Cyclin K-targeting molecular glues, their clinical application is limited by insufficient efficacy and tumor selectivity. Herein, we developed BNNC, a photomolecular glue that releases Cyclin K molecular glue (R)-CR8 and phototherapeutic agent BSS-Et in hypoxic tumor microenvironments, thereby enhancing tumor selectivity. Network pharmacology and Western blotting analysis demonstrated that the combination of (R)-CR8 and BSS-Et synergistically enhances DNA damage and apoptosis in breast cancer cells compared to either monotherapy. In vivo, BNNC exhibited potent tumor growth inhibition with excellent biosafety and biocompatibility. This intelligent design framework significantly improves the therapeutic efficacy and selectivity of molecular glues. It is expected to be generalizable to other molecular glues and phototherapeutic agents.