A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia
Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a highly aggressive hematological malignancy for which targeted therapies remain underdeveloped. Oncogenic mutations in Notch1 occur in up to 75% of T‐ALL patients. Although γ‐secretase inhibitors (GSIs) can block Notch1 activation, their clini...
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2025-08-01
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| Online Access: | https://doi.org/10.1002/advs.202505087 |
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| author | Ruinan Jia Yang Liu Jilong Xiao Yuan Xia Xin Zhao Huixian Ma Jingjing Ye Zhiyue Zhang Tao Sun Chunyan Ji |
| author_facet | Ruinan Jia Yang Liu Jilong Xiao Yuan Xia Xin Zhao Huixian Ma Jingjing Ye Zhiyue Zhang Tao Sun Chunyan Ji |
| author_sort | Ruinan Jia |
| collection | DOAJ |
| description | Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a highly aggressive hematological malignancy for which targeted therapies remain underdeveloped. Oncogenic mutations in Notch1 occur in up to 75% of T‐ALL patients. Although γ‐secretase inhibitors (GSIs) can block Notch1 activation, their clinical application is limited by side effects and reduced sensitivity. Here, a self‐assembling, reactive oxygen species (ROS)‐responsive nanotherapeutic strategy—PHD/G‐NPs—co‐loaded with GSI and controlled released dihydroartemisinin (DHA), and modified with a CD38 antibody is reported. The CD38 antibody specifically targets T‐ALL cells, while GSI selectively inhibits Notch1, resulting in a dual‐targeting approach. GSI is released first, inhibiting Notch1 activation and inducing the death of a subset of T‐ALL cells. To eliminate semi‐quiescent T‐ALL cells that escape initial therapy by elevating ROS levels, a ROS‐sensitive DHA delivery system is employed to enhance ferroptosis and boost GSI efficacy. After elucidating the mechanism of action of PHD/G‐NPs in T‐ALL cells, PHD/G‐NPs are combined with αPD‐1, which triggers an anti‐tumor immune response in vivo. This dual‐targeting strategy using CD38‐modified PHD/G‐NPs enables controlled drug release, enhances ferroptosis, mitigates GSI‐induced gastrointestinal toxicity, and improves therapeutic efficacy. This nanomedical approach offers a novel strategy for targeted T‐ALL treatment. |
| format | Article |
| id | doaj-art-9bc88fab1c054c3cad8a0444795c3f39 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-9bc88fab1c054c3cad8a0444795c3f392025-08-23T14:12:34ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202505087A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic LeukemiaRuinan Jia0Yang Liu1Jilong Xiao2Yuan Xia3Xin Zhao4Huixian Ma5Jingjing Ye6Zhiyue Zhang7Tao Sun8Chunyan Ji9Department of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan 250012 P. R. ChinaNMPA Key Laboratory for Technology Research and Evaluation of Drug Products Key Laboratory of Chemical Biology (Ministry of Education) Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics Department of Pharmaceutics School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. ChinaDepartment of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan 250012 P. R. ChinaDepartment of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan 250012 P. R. ChinaDepartment of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan 250012 P. R. ChinaCryomedicine Laboratory Qilu Hospital of Shandong University Jinan Shandong Province 250012 ChinaShandong Key Laboratory of Hematological Diseases and Immune Microenvironment Qilu Hospital Shandong University Jinan 250012 P. R. ChinaNMPA Key Laboratory for Technology Research and Evaluation of Drug Products Key Laboratory of Chemical Biology (Ministry of Education) Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics Department of Pharmaceutics School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. ChinaShandong Key Laboratory of Hematological Diseases and Immune Microenvironment Qilu Hospital Shandong University Jinan 250012 P. R. ChinaDepartment of Hematology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan 250012 P. R. ChinaAbstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a highly aggressive hematological malignancy for which targeted therapies remain underdeveloped. Oncogenic mutations in Notch1 occur in up to 75% of T‐ALL patients. Although γ‐secretase inhibitors (GSIs) can block Notch1 activation, their clinical application is limited by side effects and reduced sensitivity. Here, a self‐assembling, reactive oxygen species (ROS)‐responsive nanotherapeutic strategy—PHD/G‐NPs—co‐loaded with GSI and controlled released dihydroartemisinin (DHA), and modified with a CD38 antibody is reported. The CD38 antibody specifically targets T‐ALL cells, while GSI selectively inhibits Notch1, resulting in a dual‐targeting approach. GSI is released first, inhibiting Notch1 activation and inducing the death of a subset of T‐ALL cells. To eliminate semi‐quiescent T‐ALL cells that escape initial therapy by elevating ROS levels, a ROS‐sensitive DHA delivery system is employed to enhance ferroptosis and boost GSI efficacy. After elucidating the mechanism of action of PHD/G‐NPs in T‐ALL cells, PHD/G‐NPs are combined with αPD‐1, which triggers an anti‐tumor immune response in vivo. This dual‐targeting strategy using CD38‐modified PHD/G‐NPs enables controlled drug release, enhances ferroptosis, mitigates GSI‐induced gastrointestinal toxicity, and improves therapeutic efficacy. This nanomedical approach offers a novel strategy for targeted T‐ALL treatment.https://doi.org/10.1002/advs.202505087γ‐secretase inhibitors (GSIs)dihydroartemisinin (DHA)ferroptosisT‐cell acute lymphoblastic leukemia (T‐ALL) |
| spellingShingle | Ruinan Jia Yang Liu Jilong Xiao Yuan Xia Xin Zhao Huixian Ma Jingjing Ye Zhiyue Zhang Tao Sun Chunyan Ji A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia Advanced Science γ‐secretase inhibitors (GSIs) dihydroartemisinin (DHA) ferroptosis T‐cell acute lymphoblastic leukemia (T‐ALL) |
| title | A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia |
| title_full | A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia |
| title_fullStr | A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia |
| title_full_unstemmed | A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia |
| title_short | A ROS‐Responsive Dual‐Targeting Drug Nanocarrier Serving as a GSI Synergist and Ferroptosis Sensitizer for T‐Cell Acute Lymphoblastic Leukemia |
| title_sort | ros responsive dual targeting drug nanocarrier serving as a gsi synergist and ferroptosis sensitizer for t cell acute lymphoblastic leukemia |
| topic | γ‐secretase inhibitors (GSIs) dihydroartemisinin (DHA) ferroptosis T‐cell acute lymphoblastic leukemia (T‐ALL) |
| url | https://doi.org/10.1002/advs.202505087 |
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