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It is still a great challenge to address these issues using a single and facile design. Herein, a series of totally caged type I pro\u2010photosensitizers (Pro\u2010I\u2010PSs) are rationally developed that are only activated in tumor hypoxic environment and combine two oxygen\u2010independent therapeutic mechanisms under single\u2010pulse laser irradiation to enhance the phototherapeutic efficacy. Specifically, five benzophenothiazine\u2010based dyes modified with different nitroaromatic groups, BPN 1\u22125, are designed and explored as latent hypoxia\u2010activatable Pro\u2010I\u2010PSs. By comparing their optical responses to nitroreductase (NTR), it is identified that the 2\u2010methoxy\u20104\u2010nitrophenyl decorated dye (BPN 2) is the optimal Pro\u2010I\u2010PSs, which can achieve NTR\u2010activated background\u2010free fluorescence\/photoacoustic dual\u2010modality tumor imaging. Furthermore, upon activation, BPN 2 can simultaneously produce an oxygen\u2010independent photoacoustic cavitation effect and a photodynamic type I process at single\u2010pulse laser irradiation. Detailed studies in vitro and in vivo indicated that BPN 2 can effectively induce cancer cell apoptosis through synergistic effects. This study provides promising potential for overcoming the pitfalls of hypoxic\u2010tumor photodynamic therapy.<\/jats:p>","DOI":"10.1002\/advs.202400462","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T14:54:50Z","timestamp":1718636090000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Totally Caged Type I Pro\u2010Photosensitizer for Oxygen\u2010Independent Synergistic Phototherapy of Hypoxic Tumors"],"prefix":"10.1002","volume":"11","author":[{"given":"Qin","family":"Zeng","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Laser Life Science &amp; Institute of Laser Life Science Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University  Guangzhou 510631 China"},{"name":"The Seventh Affiliated Hospital Southern Medical University Foshan  Guangdong 528244 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