CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer
Abstract Elevated squalene epoxidase (SQLE) levels in bladder cancer cells drive abnormal cholesterol accumulation, contributing to malignancy, invasion, and resistance to immunotherapy. Here, we introduce a hollow CuO nanoparticle-based nanotherapeutic, termed CuOTeDsP, which is PEGylated and co-lo...
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| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03609-2 |
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| author | Hai Cai Panpan Xue Siyuan Liu Yaxin Ma Xuemei Zeng Shuangqian Yan Ning Xu |
| author_facet | Hai Cai Panpan Xue Siyuan Liu Yaxin Ma Xuemei Zeng Shuangqian Yan Ning Xu |
| author_sort | Hai Cai |
| collection | DOAJ |
| description | Abstract Elevated squalene epoxidase (SQLE) levels in bladder cancer cells drive abnormal cholesterol accumulation, contributing to malignancy, invasion, and resistance to immunotherapy. Here, we introduce a hollow CuO nanoparticle-based nanotherapeutic, termed CuOTeDsP, which is PEGylated and co-loaded with SQLE inhibitor terbinafine and disulfiram, for enhanced bladder cancer therapy through cholesterol metabolism modulation. CuO nanoparticles exhibit peroxidase-, catalase-, and glutathione oxidase-like enzymatic activities, along with biodegradability, resulting in elevated oxidative stress, alleviation of hypoxia, and responsive therapeutic release. Terbinafine reduces cholesterol levels in cancer cells by inhibiting SQLE, downregulating the expression of ATP7A and PD-L1, thereby promoting cellular Cu2+ accumulation and enhancing immune responses. Disulfiram further reacts with Cu2+ to form lethal bis(diethyldithiocarbamate)-copper complexes. Mechanistic studies reveal that CuOTeDsP induces cell death through a combination of cuproptosis and apoptosis, while simultaneously eliciting robust immune responses. In synergy with PD-1 monoclonal antibody, CuOTeDsP achieves a high tumor inhibition rate of 70% in a mouse bladder cancer model. This work highlights an effective strategy for bladder cancer by leveraging cuproptosis-driven immunotherapy and provides insights into the design of advanced nanotherapeutics. Graphical abstract |
| format | Article |
| id | doaj-art-cab31f95df9340deaa37a72f931f2f8b |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-cab31f95df9340deaa37a72f931f2f8b2025-08-20T04:03:07ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123112010.1186/s12951-025-03609-2CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancerHai Cai0Panpan Xue1Siyuan Liu2Yaxin Ma3Xuemei Zeng4Shuangqian Yan5Ning Xu6Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical UniversityStrait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE)Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE)Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE)Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University, Biomedical Research Center of South China, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal UniversityStrait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE)Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical UniversityAbstract Elevated squalene epoxidase (SQLE) levels in bladder cancer cells drive abnormal cholesterol accumulation, contributing to malignancy, invasion, and resistance to immunotherapy. Here, we introduce a hollow CuO nanoparticle-based nanotherapeutic, termed CuOTeDsP, which is PEGylated and co-loaded with SQLE inhibitor terbinafine and disulfiram, for enhanced bladder cancer therapy through cholesterol metabolism modulation. CuO nanoparticles exhibit peroxidase-, catalase-, and glutathione oxidase-like enzymatic activities, along with biodegradability, resulting in elevated oxidative stress, alleviation of hypoxia, and responsive therapeutic release. Terbinafine reduces cholesterol levels in cancer cells by inhibiting SQLE, downregulating the expression of ATP7A and PD-L1, thereby promoting cellular Cu2+ accumulation and enhancing immune responses. Disulfiram further reacts with Cu2+ to form lethal bis(diethyldithiocarbamate)-copper complexes. Mechanistic studies reveal that CuOTeDsP induces cell death through a combination of cuproptosis and apoptosis, while simultaneously eliciting robust immune responses. In synergy with PD-1 monoclonal antibody, CuOTeDsP achieves a high tumor inhibition rate of 70% in a mouse bladder cancer model. This work highlights an effective strategy for bladder cancer by leveraging cuproptosis-driven immunotherapy and provides insights into the design of advanced nanotherapeutics. Graphical abstracthttps://doi.org/10.1186/s12951-025-03609-2Cholesterol metabolismSQLECuproptosisBladder cancerImmunotherapy |
| spellingShingle | Hai Cai Panpan Xue Siyuan Liu Yaxin Ma Xuemei Zeng Shuangqian Yan Ning Xu CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer Journal of Nanobiotechnology Cholesterol metabolism SQLE Cuproptosis Bladder cancer Immunotherapy |
| title | CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| title_full | CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| title_fullStr | CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| title_full_unstemmed | CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| title_short | CuOTeDsP nanotherapeutics enhance cuproptosis-mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| title_sort | cuotedsp nanotherapeutics enhance cuproptosis mediated immunotherapy by modulating cholesterol metabolism in bladder cancer |
| topic | Cholesterol metabolism SQLE Cuproptosis Bladder cancer Immunotherapy |
| url | https://doi.org/10.1186/s12951-025-03609-2 |
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