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Herein, an enzyme\u2010mediated nuclear DNA\u2010targeted photogenerator (\n                    <jats:bold>\n                      P\u2010NO\n                      <jats:sub>3<\/jats:sub>\n                    <\/jats:bold>\n                    ) was constructed through dual\u2010key 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\u2010dependent 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\u2010positive pyridine groups can further competitively bind with DNA, promoting\n                    <jats:bold>\n                      P\u2010NO\n                      <jats:sub>3<\/jats:sub>\n                    <\/jats:bold>\n                    to precisely anchor and illuminate nuclear DNA (the second key). Upon cascade activation,\n                    <jats:bold>\n                      P\u2010NO\n                      <jats:sub>3<\/jats:sub>\n                    <\/jats:bold>\n                    utilized photogenerated highly toxic hydroxyl radical (\u00b7OH) in situ to damage the nucleus even under hypoxia, causing the up\u2010regulated expression of related genes (DDI2, KDM4D, RGCC). Concomitantly, damage\u2010associated high\u2010mobility 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\u2010DNA\u2010targeted phototherapeutic agents for complete ablation of metastatic tumors.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523661","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T15:49:30Z","timestamp":1772984970000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Dual\u2010Key Gated Nuclear\u2010DNA\u2010Targeted Photogenerator for Amplified Photodynamic Immunotherapy of Breast Cancer"],"prefix":"10.1002","volume":"65","author":[{"given":"Ting","family":"Wang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering School of Materials Science and Engineering Key Laboratory of Chemistry for Inorganic\/Organic Hybrid Functionalized Materials of Anhui Province Anhui University  Hefei P.R. 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