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For the first time, a glutathione (GSH)\u2010responsive metal\u2013organic framework (MOF) nanoinducer is engineered for co\u2010delivering doxorubicin (DOX) and HIF\u20101\u03b1 antisense oligonucleotide labeled with Ce6 photosensitizer. This new crystal structure exhibited robust stability in simulated physiological environments. Furthermore, multimodal synergistic effects are exhibited upon tumor cell internalization with the nanoinducer. GSH depletion synergizes with photodynamic therapy (PDT) generated reactive oxygen species (ROS) to induce ferroptosis, which effectively drives phenotypic reprogramming of M2\u2010TAMs toward M1 macrophages. HIF\u20101\u03b1 antisense oligonucleotides downregulate HIF\u20101\u03b1 expression as well as downstream P\u2010glycoprotein (P\u2010gp) mediated drug efflux, thereby significantly enhancing DOX accumulation in chemoresistant breast cancer cells. Consequently, the combination of DOX with ferroptosis\u2010induced immunogenic cell death (ICD) initiates antitumor immunity and activates cytotoxic T lymphocytes. This smart biomimetic nanoinducer demonstrates robust antitumor performance in both in vitro and in vivo models, effectively activating tumor\u2010specific immune responses. A promising candidate nanodrug with a new crystal structure is presented for chemotherapy\u2010immunotherapy combination therapy.<\/jats:p>","DOI":"10.1002\/adhm.202503437","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T08:49:47Z","timestamp":1762505387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Glutathione\u2010Depletable Nanoinducer for Boosting Immunomodulatory Synergistic Therapy to Reverse Breast Cancer Chemoresistance"],"prefix":"10.1002","volume":"15","author":[{"given":"Senyi","family":"Gong","sequence":"first","affiliation":[{"name":"School of Life Sciences and Health Engineering Jiangnan University  Wuxi 214122 China"},{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai 200237 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