Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer
Abstract In colorectal cancer treatment, chemotherapeutic agents induce reactive oxygen species (ROS) production, which promotes NAD+ accumulation in tumor cells, reducing treatment sensitivity and worsening patient prognosis. Targeted depletion of NAD+ presents a promising strategy to overcome tumo...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-025-03417-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849309705561702400 |
|---|---|
| author | Dong Zhong Xiaoxin Yang Jinhui Yang Zhisheng Luo Zhichao Feng Mengtian Ma Yunjie Liao Yongxiang Tang Yu Wen Jun Liu Shuo Hu |
| author_facet | Dong Zhong Xiaoxin Yang Jinhui Yang Zhisheng Luo Zhichao Feng Mengtian Ma Yunjie Liao Yongxiang Tang Yu Wen Jun Liu Shuo Hu |
| author_sort | Dong Zhong |
| collection | DOAJ |
| description | Abstract In colorectal cancer treatment, chemotherapeutic agents induce reactive oxygen species (ROS) production, which promotes NAD+ accumulation in tumor cells, reducing treatment sensitivity and worsening patient prognosis. Targeted depletion of NAD+ presents a promising strategy to overcome tumor resistance and improve patient prognosis. Here, we designed a dual-metallic nanozyme (CuMnOx−V@Oxa@SP) with defect engineering, modified by soy phospholipids (SP) and loaded with oxaliplatin (Oxa). This nanozyme uses its oxygen-deficient active sites to rapidly and irreversibly degrade NAD⁺ and NADH into nicotinamide and ADP-ribose derivatives, disrupting the electron transport chain (ETC) and compromising tumor antioxidant defenses. It also inhibits the glutathione S-transferase P1 (GSTP1) pathway, weakening tumor detoxification and enhancing chemotherapy sensitivity. Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the CuMnOx−V nanozymes with excellent catalytic activity. In the tumor microenvironment (TME), CuMnOx−V nanozymes exhibit peroxidase, oxidase, and NAD+ oxidase-mimicking activities. CuMnOx−V generates multiple ROS and depletes NAD+ while preventing their regeneration thereby triggering a cascade amplification of oxidative stress. This, coupled with targeted chemotherapy drug delivery, restores chemosensitivity in refractory tumors and exposes the vulnerabilities of resistant colorectal cancer cells to ROS. |
| format | Article |
| id | doaj-art-2ae2df412c8c4d69b6b8517d35a61a3e |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-2ae2df412c8c4d69b6b8517d35a61a3e2025-08-20T03:53:58ZengBMCJournal of Nanobiotechnology1477-31552025-05-0123112310.1186/s12951-025-03417-8Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancerDong Zhong0Xiaoxin Yang1Jinhui Yang2Zhisheng Luo3Zhichao Feng4Mengtian Ma5Yunjie Liao6Yongxiang Tang7Yu Wen8Jun Liu9Shuo Hu10Department of Nuclear Medicine, Xiangya Hospital, Central South UniversityDepartment of Radiology, Second Xiangya Hospital of Central South UniversityDepartment of Nuclear Medicine, Xiangya Hospital, Central South UniversityDepartment of Nuclear Medicine, Xiangya Hospital, Central South UniversitySJTU-Ruijin-UIH Institute for Medical Imaging Technology Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Radiology, The First Hospital of Hunan University of Chinese MedicineDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Nuclear Medicine, Xiangya Hospital, Central South UniversityFurong Laboratory, Central South UniversityDepartment of Radiology, Second Xiangya Hospital of Central South UniversityDepartment of Nuclear Medicine, Xiangya Hospital, Central South UniversityAbstract In colorectal cancer treatment, chemotherapeutic agents induce reactive oxygen species (ROS) production, which promotes NAD+ accumulation in tumor cells, reducing treatment sensitivity and worsening patient prognosis. Targeted depletion of NAD+ presents a promising strategy to overcome tumor resistance and improve patient prognosis. Here, we designed a dual-metallic nanozyme (CuMnOx−V@Oxa@SP) with defect engineering, modified by soy phospholipids (SP) and loaded with oxaliplatin (Oxa). This nanozyme uses its oxygen-deficient active sites to rapidly and irreversibly degrade NAD⁺ and NADH into nicotinamide and ADP-ribose derivatives, disrupting the electron transport chain (ETC) and compromising tumor antioxidant defenses. It also inhibits the glutathione S-transferase P1 (GSTP1) pathway, weakening tumor detoxification and enhancing chemotherapy sensitivity. Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the CuMnOx−V nanozymes with excellent catalytic activity. In the tumor microenvironment (TME), CuMnOx−V nanozymes exhibit peroxidase, oxidase, and NAD+ oxidase-mimicking activities. CuMnOx−V generates multiple ROS and depletes NAD+ while preventing their regeneration thereby triggering a cascade amplification of oxidative stress. This, coupled with targeted chemotherapy drug delivery, restores chemosensitivity in refractory tumors and exposes the vulnerabilities of resistant colorectal cancer cells to ROS.https://doi.org/10.1186/s12951-025-03417-8ETC disruptionBimetallic nanozymesNAD+ depletionMulti-enzyme activityOxaliplatin resistance |
| spellingShingle | Dong Zhong Xiaoxin Yang Jinhui Yang Zhisheng Luo Zhichao Feng Mengtian Ma Yunjie Liao Yongxiang Tang Yu Wen Jun Liu Shuo Hu Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer Journal of Nanobiotechnology ETC disruption Bimetallic nanozymes NAD+ depletion Multi-enzyme activity Oxaliplatin resistance |
| title | Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| title_full | Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| title_fullStr | Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| title_full_unstemmed | Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| title_short | Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| title_sort | oxygen vacancy engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi enzyme activity to reverse oxaliplatin resistance in colorectal cancer |
| topic | ETC disruption Bimetallic nanozymes NAD+ depletion Multi-enzyme activity Oxaliplatin resistance |
| url | https://doi.org/10.1186/s12951-025-03417-8 |
| work_keys_str_mv | AT dongzhong oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT xiaoxinyang oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT jinhuiyang oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT zhishengluo oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT zhichaofeng oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT mengtianma oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT yunjieliao oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT yongxiangtang oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT yuwen oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT junliu oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer AT shuohu oxygenvacancyengineeredbimetallicnanozymesfordisruptingelectrontransportchainandsynergisticmultienzymeactivitytoreverseoxaliplatinresistanceincolorectalcancer |