A Dual-Key Gated Nuclear-DNA-Targeted Photogenerator for Amplified Photodynamic Immunotherapy of Breast Cancer.

Developing therapeutic agents that are capable of directly damaging nuclear DNA is critical for curing metastatic breast cancer. Herein, an enzyme-mediated nuclear DNA-targeted photogenerator (P-NO3) was constructed through dual-key gating for amplified photodynamic immunotherapy (PDIT) against breast cancer, which has rarely been reported. Specifically, bilateral pyridinone units were included in the design to interact with overactivated cyclin-dependent kinases 4 and 6 (CDK4/6) within breast cancer cells, which can circumvent the limitation of an impermeable nuclear envelope (the first key). Once inside the nucleus, the equipped dual-positive pyridine groups can further competitively bind with DNA, promoting P-NO3 to precisely anchor and illuminate nuclear DNA (the second key). Upon cascade activation, P-NO3 utilized photogenerated highly toxic hydroxyl radical (·OH) in situ to damage the nucleus even under hypoxia, causing the up-regulated expression of related genes (DDI2, KDM4D, RGCC). Concomitantly, damage-associated high-mobility group box 1 (HMGB1) and calreticulin (CRT) were released, triggering a systemic immune response to further suppress distant tumors, realizing efficient PDIT for breast cancer. This study provides new insight into designing nuclear-DNA-targeted phototherapeutic agents for complete ablation of metastatic tumors.