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The negligible oxygen\u2010dependent nature of type I photosensitizers (PSs) has made them appropriate candidates for the treatment of hypoxic tumors. However, the lack of effective molecular design approaches, the phototoxicity of PSs to normal tissue before and after treatment, and the drawbacks of poor hydrophilicity severely hinder the development of PSs in hypoxic tumor therapy. Thus, developing a hydrophilic PS with good hypoxia resistance and minimal side effects is an urgent but challenging problem. Herein, we present a nanotheranostic (\n                    <jats:bold>NanoPcN8O<\/jats:bold>\n                    ) based on the self\u2010assembly of a hydrophilic phthalocyanine derivative (\n                    <jats:bold>PcN8O<\/jats:bold>\n                    ), a hypoxia\u2010responsive bioreductive phototherapeutic agent suitable for activatable photoacoustic (PA) imaging and tumor therapy. Hypoxic regions in various tumors exhibit strong reductive capability, and only in such conditions did\n                    <jats:bold>NanoPcN8O<\/jats:bold>\n                    feature multiple\n                    <jats:italic>N<\/jats:italic>\n                    \u2010oxide groups that could be bioreduced to yield the product\n                    <jats:bold>NanoPcN8<\/jats:bold>\n                    with abundant electron\u2010rich tertiary amine groups, which switches on the type I photodynamic and photothermal effects, facilitating the generation of type I reactive oxygen species (ROS) and heat. Better still,\n                    <jats:bold>NanoPcN8O<\/jats:bold>\n                    achieved hypoxia\u2010induced selective PA imaging in a preclinical model. Based on these merits, the hypoxia\u2010induced switchable type I photodynamic therapy (PDT) and photothermal therapy (PTT) strategies demonstrated remarkable phototherapeutic efficiency with high biosafety. This delicate design is anticipated to offer a novel and safe strategy to overcome hypoxia resistance in phototherapeutics.\n                  <\/jats:p>","DOI":"10.1002\/anie.202506412","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T22:26:46Z","timestamp":1744237606000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["A Hypoxia\u2010Triggered Bioreduction of Hydrophilic Type I Photosensitizer for Switchable In Vivo Photoacoustic Imaging and High\u2010Specificity Cancer Phototherapy"],"prefix":"10.1002","volume":"64","author":[{"given":"Yuan\u2010Yuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of Chemistry Fuzhou University  Fuzhou 350108 China"},{"name":"Department of Chemistry and Nanoscience Ewha Womans University  Seoul 03760 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihui","family":"Xu","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of Chemistry Fuzhou University  Fuzhou 350108 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of Chemistry Fuzhou University  Fuzhou 350108 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of Chemistry Fuzhou University  Fuzhou 350108 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Nanoscience Ewha Womans University  Seoul 03760 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingshu","family":"Li","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of Chemistry Fuzhou University  Fuzhou 350108 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juyoung","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Nanoscience Ewha Womans University  Seoul 03760 South Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul 03760 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00525"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2540"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1367"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CS00304A"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00055376"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.2c00531"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6CS00616G"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2021.213888"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202103978"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2023.215560"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12040163"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201814730"},{"key":"e_1_2_7_13_1","first-page":"3110","volume":"47","author":"Henderson B. 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