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Hydrogen\u2010bonded organic frameworks (HOFs) are successfully used for the protective encapsulation of proteins; however, easy precipitation and lack of controlled release of existing HOFs limit their further application for protein delivery in vivo. Here, a hypoxia\u2010responsive HOF, self\u2010assembled from azobenzenedicarboxylate\/polyethylene glycol\u2010conjugated azobenzenedicarboxylate and tetrakis(4\u2010amidiniumphenyl)methane through charge\u2010assisted hydrogen\u2010bonding, is developed for systemic protein delivery to tumor cells. The newly generated HOF platform efficiently encapsulates representative cytochrome C, demonstrating good dispersibility under physiological conditions. Moreover, it can respond to overexpressed reductases in the cytoplasm under hypoxic conditions, inducing fast intracellular protein release to exert therapeutic effects. The strategy presented herein can be applied to other therapeutic proteins and can be expanded to encompass more intrinsic tumor microenvironment stimuli. This offers a novel avenue for utilizing HOFs in protein\u2010based cancer therapy.<\/jats:p>","DOI":"10.1002\/adhm.202400747","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T13:48:12Z","timestamp":1713880092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hypoxia\u2010Responsive Hydrogen\u2010Bonded Organic Framework\u2010Mediated Protein Delivery for Cancer Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Xu","family":"He","sequence":"first","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  GuangRong Dao 8 Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute &amp; Hospital National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin\u2019s Clinical Research Center for Cancer  Tianjin 300060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  GuangRong Dao 8 Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyu","family":"Niu","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  GuangRong Dao 8 Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6901-4281","authenticated-orcid":false,"given":"Zhiqiang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  GuangRong Dao 8 Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banglin","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Polymer Materials College of Chemistry and Materials Science Fujian Normal University  Fuzhou 350117 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Xiong","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute &amp; 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