A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies
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Wiley Open Access
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| Natura: | Artículo Open Access |
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Wiley
2025
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| _version_ | 1867012802705620993 |
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| author | Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu |
| author_facet | Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu |
| collection | Wiley Open Access |
| contents | A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu Advanced Healthcare Materials Abstract Metal ion dyshomeostasis represents a therapeutic vulnerability in cancer, yet simultaneous targeting of multiple metal‐dependent death pathways remains challenging. Herein, a pH‐responsive copper‐based metal‐organic framework nanoplatform (Cu‐MOF@DPCPX) is engineered to co‐trigger cuproptosis, ferroptosis, and mitophagy through tumor‐specific copper overload. The system leverages acidic tumor microenvironments for targeted degradation, releasing Cu 2 ⁺. The liberated Cu 2 ⁺ depletes overexpressed glutathione (GSH) to disrupt redox homeostasis and generates toxic Cu⁺ that initiates dual catalytic cycles. 1) Cu⁺ accumulation promotes lipoylated protein aggregation and Fe‐S cluster loss, driving cuproptosis; 2) Cu⁺‐mediated Fenton‐like reactions convert endogenous H 2 O 2 into hydroxyl radicals (·OH) and downregulate GPX4 to induce ferroptosis. Crucially, mitochondrial damage from these pathways activates mitophagy, which releases sequestered copper to establish a self‐amplifying death cascade. In vivo, Cu‐MOF@DPCPX demonstrates potent tumor suppression across multiple tumor models (4T1‐breast, LLC‐lung, PAN02‐pancreatic, GL261‐glioblastoma), while reprogramming immunosuppressive microenvironments via increased CD8⁺ T‐cell infiltration and M1 macrophage polarization. This triple‐pathway activation strategy overcomes monotherapy limitations and establishes a paradigm for metal‐ion‐based multimodal oncotherapy. 10.1002/adhm.202503530 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/adhm.202503530 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_adhm_202503530 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu Advanced Healthcare Materials A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies Kun Deng Wei Gao Yu Wen Jianliang Huang Xuetong Li Xiaoxin Yang Minghua Wu Advanced Healthcare Materials Abstract Metal ion dyshomeostasis represents a therapeutic vulnerability in cancer, yet simultaneous targeting of multiple metal‐dependent death pathways remains challenging. Herein, a pH‐responsive copper‐based metal‐organic framework nanoplatform (Cu‐MOF@DPCPX) is engineered to co‐trigger cuproptosis, ferroptosis, and mitophagy through tumor‐specific copper overload. The system leverages acidic tumor microenvironments for targeted degradation, releasing Cu 2 ⁺. The liberated Cu 2 ⁺ depletes overexpressed glutathione (GSH) to disrupt redox homeostasis and generates toxic Cu⁺ that initiates dual catalytic cycles. 1) Cu⁺ accumulation promotes lipoylated protein aggregation and Fe‐S cluster loss, driving cuproptosis; 2) Cu⁺‐mediated Fenton‐like reactions convert endogenous H 2 O 2 into hydroxyl radicals (·OH) and downregulate GPX4 to induce ferroptosis. Crucially, mitochondrial damage from these pathways activates mitophagy, which releases sequestered copper to establish a self‐amplifying death cascade. In vivo, Cu‐MOF@DPCPX demonstrates potent tumor suppression across multiple tumor models (4T1‐breast, LLC‐lung, PAN02‐pancreatic, GL261‐glioblastoma), while reprogramming immunosuppressive microenvironments via increased CD8⁺ T‐cell infiltration and M1 macrophage polarization. This triple‐pathway activation strategy overcomes monotherapy limitations and establishes a paradigm for metal‐ion‐based multimodal oncotherapy. 10.1002/adhm.202503530 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies |
| topic | Advanced Healthcare Materials |
| url | https://advanced.onlinelibrary.wiley.com/doi/10.1002/adhm.202503530 |