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To date, numerous optical probes have been reported for NTRs detection. Approaches capable of concisely guiding the probe design of NTRs suitable for deep\u2010tissue imaging, however, are still lacking. As such, direct optical imaging of endogenous NTR activities from tumors derived from cancer patients is thus far not possible. Herein, aided by computational calculations, the authors have successfully developed a series of two\u2010photon (TP) small\u2010molecule fluorogenic probes capable of sensitively detecting general NTR activities from various biological samples; by optimizing the distance between the recognition moiety and the reactive site of NTRs from different sources, the authors have discovered and experimentally proven that <jats:bold>X4<\/jats:bold> displays the best performance in both sensitivity and selectivity. Furthermore, <jats:bold>X4<\/jats:bold> shows excellent TP excited fluorescence properties capable of directly monitoring\/imaging endogenous NTR activities from live mammalian cells, growing zebrafish, and tumor\u2010bearing mice. Finally, with an outstanding TP tissue\u2010penetrating imaging property, <jats:bold>X4<\/jats:bold> is used, for the first time, to successfully detect endogenous NTR activities from the liver lysates and cardia tissues of a cancer patient. The work may provide a universal strategy to design novel TP small\u2010molecule enzymatic probes in future clinical applications.<\/jats:p>","DOI":"10.1002\/adhm.202200400","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T06:26:59Z","timestamp":1651213619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Two\u2010Photon Small\u2010Molecule Fluorogenic Probes for Visualizing Endogenous Nitroreductase Activities from Tumor Tissues of a Cancer Patient"],"prefix":"10.1002","volume":"11","author":[{"given":"Changmin","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Flexible Electronics (KLOFE) &amp; Institute of Advanced Materials (IAM) Nanjing Tech University (NanjingTech)  Nanjing 211816 P. R. China"},{"name":"State Key Laboratory of Coordination Chemistry Nanjing University  Nanjing 210023 P. R. 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