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

ABSTRACT 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‐NO 3 ) 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‐NO 3 to precisely anchor and illuminate nuclear DNA (the second key). Upon cascade activation, P‐NO 3 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.