Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy
Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis...
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Elsevier
2025-05-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525001480 |
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| author | Muhammad Hamza Shuai Wang Hao Wu Jiayi Sun Yang Du Chuting Zeng Yike Liu Kun Li Xili Zhu Huiying Liu Lin Chen Motao Zhu |
| author_facet | Muhammad Hamza Shuai Wang Hao Wu Jiayi Sun Yang Du Chuting Zeng Yike Liu Kun Li Xili Zhu Huiying Liu Lin Chen Motao Zhu |
| author_sort | Muhammad Hamza |
| collection | DOAJ |
| description | Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe–S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy. |
| format | Article |
| id | doaj-art-97ba3a747e2d456793aebed909ebee63 |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-97ba3a747e2d456793aebed909ebee632025-08-20T01:49:58ZengElsevierActa Pharmaceutica Sinica B2211-38352025-05-011552640265410.1016/j.apsb.2025.03.014Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapyMuhammad Hamza0Shuai Wang1Hao Wu2Jiayi Sun3Yang Du4Chuting Zeng5Yike Liu6Kun Li7Xili Zhu8Huiying Liu9Lin Chen10Motao Zhu11CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, ChinaCollege of Pulmonary and Critical Care Medicine, the 8th Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Corresponding authors.CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors.CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors.Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe–S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.http://www.sciencedirect.com/science/article/pii/S2211383525001480CuproptosisElesclomolAntioxidant protein 1 siRNAOuter membrane vesicleAkkermansia muciniphilaTumor microenvironment |
| spellingShingle | Muhammad Hamza Shuai Wang Hao Wu Jiayi Sun Yang Du Chuting Zeng Yike Liu Kun Li Xili Zhu Huiying Liu Lin Chen Motao Zhu Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy Acta Pharmaceutica Sinica B Cuproptosis Elesclomol Antioxidant protein 1 siRNA Outer membrane vesicle Akkermansia muciniphila Tumor microenvironment |
| title | Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy |
| title_full | Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy |
| title_fullStr | Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy |
| title_full_unstemmed | Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy |
| title_short | Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy |
| title_sort | targeting copper homeostasis akkermansia derived omvs co deliver atox1 sirna and elesclomol for cancer therapy |
| topic | Cuproptosis Elesclomol Antioxidant protein 1 siRNA Outer membrane vesicle Akkermansia muciniphila Tumor microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525001480 |
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