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Oncogenic mutations in\u00a0Notch1\u00a0occur in up to 75% of T\u2010ALL patients. Although \u03b3\u2010secretase inhibitors (GSIs) can block\u00a0Notch1\u00a0activation, their clinical application is limited by side effects and reduced sensitivity. Here, a self\u2010assembling, reactive oxygen species (ROS)\u2010responsive nanotherapeutic strategy\u2014PHD\/G\u2010NPs\u2014co\u2010loaded with GSI and controlled released dihydroartemisinin (DHA), and modified with a CD38 antibody is reported. The CD38 antibody specifically targets T\u2010ALL cells, while GSI selectively inhibits\u00a0Notch1, resulting in a dual\u2010targeting approach. GSI is released first, inhibiting\u00a0Notch1\u00a0activation and inducing the death of a subset of T\u2010ALL cells. To eliminate semi\u2010quiescent T\u2010ALL cells that escape initial therapy by elevating ROS levels, a ROS\u2010sensitive DHA delivery system is employed to enhance ferroptosis and boost GSI efficacy. After elucidating the mechanism of action of PHD\/G\u2010NPs in T\u2010ALL cells, PHD\/G\u2010NPs are combined with \u03b1PD\u20101, which triggers an anti\u2010tumor immune response in vivo. This dual\u2010targeting strategy using CD38\u2010modified PHD\/G\u2010NPs enables controlled drug release, enhances ferroptosis, mitigates GSI\u2010induced gastrointestinal toxicity, and improves therapeutic efficacy. This nanomedical approach offers a novel strategy for targeted T\u2010ALL treatment.<\/jats:p>","DOI":"10.1002\/advs.202505087","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T08:57:03Z","timestamp":1748681823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A ROS\u2010Responsive Dual\u2010Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T\u2010Cell Acute Lymphoblastic Leukemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Ruinan","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. 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