Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer, as a subtype with high invasiveness and poor prognosis, faces issues of intertumoral heterogeneity and signaling pathway dysregulation leading to trastuzumab resistance in clinical treatment. Therefore, innovative therapeutic s...
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KeAi Communications Co., Ltd.
2025-10-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25002695 |
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| author | Jingchao Gao Tong Ye Hongkun Miao Mingjiang Liu Li Wen Yi Tian Zhiguang Fu Li Sun Lihong Wang Yu Wang |
| author_facet | Jingchao Gao Tong Ye Hongkun Miao Mingjiang Liu Li Wen Yi Tian Zhiguang Fu Li Sun Lihong Wang Yu Wang |
| author_sort | Jingchao Gao |
| collection | DOAJ |
| description | Human epidermal growth factor receptor 2 positive (HER2+) breast cancer, as a subtype with high invasiveness and poor prognosis, faces issues of intertumoral heterogeneity and signaling pathway dysregulation leading to trastuzumab resistance in clinical treatment. Therefore, innovative therapeutic strategies are urgently needed to enhance treatment efficacy and improve patient prognosis. In this study, we proposed an antibody-targeted nanoplatform responsive to the tumor microenvironment, aiming to induce ferroptosis in HER2+ breast cancer cells and thereby enhance the sensitivity to HER2-targeted drugs. Fe-MOF@Erastin@Herceptin (FEH) was prepared by loading Erastin onto mesoporous Fe-MOF and modifying it with trastuzumab (a HER2+ breast cancer cell-specific antibody). This platform gradually releases trastuzumab, Erastin, and Fe3+ in the tumor microenvironment. The modification of trastuzumab enhances tumor cell targeting while reducing toxicity to non-target cells and tissues. Erastin inhibits system XC− to reduce glutathione (GSH) synthesis. Fe3+ consumes glutathione and reduces itself to Fe2+ via a reduction reaction, which further enhances the catalytic effect of H2O2 and triggers the Fenton reaction to generate large amounts of reactive oxygen species (ROS). In the antibody-targeted cascade reaction, decreased intracellular GSH content and increased Fe2+ and ROS can further promote lipid peroxidation and down-regulation of glutathione peroxidase 4 (GPX4) in breast cancer cells, inducing ferroptosis. The experimental results indicate that FEH can significantly improve the tumor microenvironment by enhancing ferroptosis effects, providing a potential new strategy for precision therapy of HER2+ breast cancer cells. |
| format | Article |
| id | doaj-art-f024f9027fb94ee0aa617c1a5aa534b6 |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-f024f9027fb94ee0aa617c1a5aa534b62025-08-24T05:13:49ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-10-015270271810.1016/j.bioactmat.2025.06.034Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancerJingchao Gao0Tong Ye1Hongkun Miao2Mingjiang Liu3Li Wen4Yi Tian5Zhiguang Fu6Li Sun7Lihong Wang8Yu Wang9Department of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, ChinaDepartment of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, China; Corresponding author. Department of Medical Oncology, Air Force Medical Center, The Fourth Military Medical University, PLA, No.30 Fucheng Road, Haidian District, Beijing, 100142, China.Human epidermal growth factor receptor 2 positive (HER2+) breast cancer, as a subtype with high invasiveness and poor prognosis, faces issues of intertumoral heterogeneity and signaling pathway dysregulation leading to trastuzumab resistance in clinical treatment. Therefore, innovative therapeutic strategies are urgently needed to enhance treatment efficacy and improve patient prognosis. In this study, we proposed an antibody-targeted nanoplatform responsive to the tumor microenvironment, aiming to induce ferroptosis in HER2+ breast cancer cells and thereby enhance the sensitivity to HER2-targeted drugs. Fe-MOF@Erastin@Herceptin (FEH) was prepared by loading Erastin onto mesoporous Fe-MOF and modifying it with trastuzumab (a HER2+ breast cancer cell-specific antibody). This platform gradually releases trastuzumab, Erastin, and Fe3+ in the tumor microenvironment. The modification of trastuzumab enhances tumor cell targeting while reducing toxicity to non-target cells and tissues. Erastin inhibits system XC− to reduce glutathione (GSH) synthesis. Fe3+ consumes glutathione and reduces itself to Fe2+ via a reduction reaction, which further enhances the catalytic effect of H2O2 and triggers the Fenton reaction to generate large amounts of reactive oxygen species (ROS). In the antibody-targeted cascade reaction, decreased intracellular GSH content and increased Fe2+ and ROS can further promote lipid peroxidation and down-regulation of glutathione peroxidase 4 (GPX4) in breast cancer cells, inducing ferroptosis. The experimental results indicate that FEH can significantly improve the tumor microenvironment by enhancing ferroptosis effects, providing a potential new strategy for precision therapy of HER2+ breast cancer cells.http://www.sciencedirect.com/science/article/pii/S2452199X25002695FerroptosisNano-materialsGPX4SLC7A11HER2-positive breast cancer |
| spellingShingle | Jingchao Gao Tong Ye Hongkun Miao Mingjiang Liu Li Wen Yi Tian Zhiguang Fu Li Sun Lihong Wang Yu Wang Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer Bioactive Materials Ferroptosis Nano-materials GPX4 SLC7A11 HER2-positive breast cancer |
| title | Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer |
| title_full | Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer |
| title_fullStr | Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer |
| title_full_unstemmed | Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer |
| title_short | Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer |
| title_sort | antibody functionalized iron based nanoplatform for ferroptosis augmented targeted therapy of her2 positive breast cancer |
| topic | Ferroptosis Nano-materials GPX4 SLC7A11 HER2-positive breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25002695 |
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