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Metal-free hydrogen-bonded organic frameworks (HOFs) are porous materials formed by hydrogen bonds between organic components. They possess excellent biocompatibility and enzyme compatibility in biomedical applications. However, the fabrication of multi-enzyme cascading antioxidant nanoenzymes using HOFs for the treatment of cerebral ischemia-reperfusion injury (CIRI) remains challenging. Here, selenium-containing nanohydrogen-bonded organic frameworks (SeHOFs) were synthesized as glutathione peroxidase mimics, in situ encapsulating superoxide dismutase (SOD) and catalase (CAT), to form a hybrid cascading antioxidant system (SeHOF@CAT@SOD). SeHOFs exhibit enhanced catalytic activity, maintain enzyme functionality, and can protect them from temperature, proteolysis, and denaturation. Metal-free nanoenzymes demonstrate excellent biocompatibility and cascading catalytic efficacy, capable of eliminating reactive oxygen species and reducing cell apoptosis and iron depletion in vitro. Peptide modification enhances the accumulation at the infarcted site, effectively reducing the infarct volume, oxidative stress, neuronal apoptosis, iron depletion, and inflammation in the CIRI model. This study highlights the potential of nanohydrogen-bonded organic frameworks as a scaffold for the development of advanced therapeutic nanoenzymes in ischemic stroke treatment. The research first designed and synthesized selenium-doped nanohydrogen-bonded organic frameworks. This material forms a porous structure through self-assembly of organic molecules via hydrogen bonds, without metal ions, and has good biocompatibility and enzyme compatibility. More importantly, the introduction of selenium elements enables it to simulate the activity of the important antioxidant enzyme in the human body - glutathione peroxidase. Based on this, the researchers encapsulated two natural antioxidant enzymes - superoxide dismutase and catalase - into this framework to construct a hybrid cascading antioxidant nanoenzyme called SeHOF@CAT@SOD.
The ingenious aspect of this design lies in integrating the advantages of artificial nanoenzymes and natural enzymes. Experiments show that this nanoframe not only maintains the high activity of the encapsulated enzymes (retaining approximately 83.5% and 92% of their activity respectively), but also provides strong protection for the enzymes, allowing them to remain stable under harsh conditions such as high temperature, proteolysis, and denaturants. Its porous structure facilitates the free entry and exit of small molecule substrates such as reactive oxygen species, ensuring efficient catalytic reactions.
