Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging
Abstract Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employ a genetic engineering strategy to gener...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56414-8 |
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| author | Qiqi Liu Zhanxia Gao Xiangyun Zhang Qiannan Duan Yue Zhang Adam C. Midgley Li Jiao Ruming Liu Mingsheng Zhu Deling Kong Jie Zhuang Xinglu Huang |
| author_facet | Qiqi Liu Zhanxia Gao Xiangyun Zhang Qiannan Duan Yue Zhang Adam C. Midgley Li Jiao Ruming Liu Mingsheng Zhu Deling Kong Jie Zhuang Xinglu Huang |
| author_sort | Qiqi Liu |
| collection | DOAJ |
| description | Abstract Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employ a genetic engineering strategy to generate ionizable ferritin nanocages (iFTn), enabling their escape from endo-lysosomes and entry into the cytoplasm. Specifically, ionizable repeated Histidine-Histidine-Glutamic acid (9H2E) sequences are genetically incorporated into the outer surface of human heavy chain FTn, followed by the assembly of various chain-like nanostructures via a two-armed polyethylene glycol (PEG). Utilizing endosome-escaping ability, we design iFTn-based tetrameric cascade nanozymes with high superoxide dismutase- and catalase-mimicking activities. The in vivo protective effects of these ionizable cascade nanozymes against cardiac oxidative injury are demonstrated in female mouse models of cardiac ischemia-reperfusion (IR). RNA-sequencing analysis highlight the crucial role of these nanozymes in modulating superoxide anions-, hydrogen peroxide- and mitochondrial functions-relevant genes in IR injured cardiac tissue. These genetically engineered ionizable protein nanocarriers provide opportunities for developing ionizable drug delivery systems. |
| format | Article |
| id | doaj-art-1a3c33651288445f9b30b4c8bb1617b8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1a3c33651288445f9b30b4c8bb1617b82025-02-02T12:31:17ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-025-56414-8Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide ScavengingQiqi Liu0Zhanxia Gao1Xiangyun Zhang2Qiannan Duan3Yue Zhang4Adam C. Midgley5Li Jiao6Ruming Liu7Mingsheng Zhu8Deling Kong9Jie Zhuang10Xinglu Huang11School of Medicine, Nankai UniversitySchool of Medicine, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityTianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversitySchool of Medicine, Nankai UniversityKey Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, and Frontier of Science Center for Cell Response, Nankai UniversityAbstract Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employ a genetic engineering strategy to generate ionizable ferritin nanocages (iFTn), enabling their escape from endo-lysosomes and entry into the cytoplasm. Specifically, ionizable repeated Histidine-Histidine-Glutamic acid (9H2E) sequences are genetically incorporated into the outer surface of human heavy chain FTn, followed by the assembly of various chain-like nanostructures via a two-armed polyethylene glycol (PEG). Utilizing endosome-escaping ability, we design iFTn-based tetrameric cascade nanozymes with high superoxide dismutase- and catalase-mimicking activities. The in vivo protective effects of these ionizable cascade nanozymes against cardiac oxidative injury are demonstrated in female mouse models of cardiac ischemia-reperfusion (IR). RNA-sequencing analysis highlight the crucial role of these nanozymes in modulating superoxide anions-, hydrogen peroxide- and mitochondrial functions-relevant genes in IR injured cardiac tissue. These genetically engineered ionizable protein nanocarriers provide opportunities for developing ionizable drug delivery systems.https://doi.org/10.1038/s41467-025-56414-8 |
| spellingShingle | Qiqi Liu Zhanxia Gao Xiangyun Zhang Qiannan Duan Yue Zhang Adam C. Midgley Li Jiao Ruming Liu Mingsheng Zhu Deling Kong Jie Zhuang Xinglu Huang Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging Nature Communications |
| title | Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging |
| title_full | Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging |
| title_fullStr | Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging |
| title_full_unstemmed | Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging |
| title_short | Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging |
| title_sort | assembly of genetically engineered ionizable protein nanocage based nanozymes for intracellular superoxide scavenging |
| url | https://doi.org/10.1038/s41467-025-56414-8 |
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