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Herein, we rationally designed the smart molecule <jats:bold>ER\u2010ZS<\/jats:bold> for endoplasmic reticulum (ER)\u2010targeted diagnosis and treatment in cell and animal models by combining hemicyanine dyes with ER\u2010targeted functional groups (<jats:italic>p<\/jats:italic>\u2010toluenesulfonamide). Owing to its ability to target the ER with a highly specific response to viscosity, <jats:bold>ER\u2010ZS<\/jats:bold> demonstrated substantial fluorescence turn\u2010on only after binding to the ER, independent of other physiological environments. In addition, <jats:bold>ER\u2010ZS<\/jats:bold>, being a small molecule, allows for the diagnosis of nonalcoholic fatty liver disease (NAFLD) via liver imaging based on high ER stress. Importantly, <jats:bold>ER\u2010ZS<\/jats:bold> is a type\u2005I photosensitizer, producing O<jats:sub>2<\/jats:sub>\u22c5<jats:sup>\u2212<\/jats:sup> and \u22c5OH under light irradiation. Thus, after irradiating for a certain period, the photodynamic therapy inflicted severe oxidative damage to the ER of tumor cells in hypoxic (2\u2009% O<jats:sub>2<\/jats:sub>) conditions and activated the unique pyroptosis pathway, demonstrating excellent antitumor capacity in xenograft tumor models. Hence, the proposed strategy will likely shed new light on integrating molecular optics for NAFLD diagnosis and cancer therapy.<\/jats:p>","DOI":"10.1002\/anie.202316487","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:24:00Z","timestamp":1704878640000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":184,"title":["An ER\u2010targeted, Viscosity\u2010sensitive Hemicyanine Dye for the Diagnosis of Nonalcoholic Fatty Liver and Photodynamic Cancer Therapy by Activating Pyroptosis Pathway"],"prefix":"10.1002","volume":"63","author":[{"given":"Shuang","family":"Zeng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"},{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Nanoscience Ewha Womans University  03760 Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosheng","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maojun","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichu","family":"Yu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves S.","family":"Kafuti","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixian","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"},{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"},{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing School of Bioengineering Dalian University of Technology  2 Linggong Road, Hi-tech Zone 116024 Dalian China"},{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Cancer Hospital of Dalian University of Technology Liaoning Cancer Hospital &amp; 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