Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging

Qiqi Liu, Zhanxia Gao, Xiangyun Zhang, Qiannan Duan, Yue Zhang, Adam C. Midgley, Li Jiao, Ruming Liu, Mingsheng Zhu, Deling Kong (kongdeling@nankai.edu.cn), Jie Zhuang (zhuangj@nankai.edu.cn) and Xinglu Huang (huangxinglu@nankai.edu.cn)
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Qiqi Liu: Nankai University
Zhanxia Gao: Nankai University
Xiangyun Zhang: Nankai University
Qiannan Duan: Nankai University
Yue Zhang: Tianjin Medical University
Adam C. Midgley: Nankai University
Li Jiao: Nankai University
Ruming Liu: Nankai University
Mingsheng Zhu: Nankai University
Deling Kong: Nankai University
Jie Zhuang: Nankai University
Xinglu Huang: Nankai University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56414-8

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