Selenium-Containing Nanoscale Hydrogen-Bonded Organic Framework Nanozymes for Multienzyme Cascade Antioxidant-Targeted Therapy of Cerebral Ischemia–Reperfusion Injury

Metal-free hydrogen-bonded organic frameworks (HOFs) are porous materials formed via hydrogen bonding of organic building blocks, offering excellent biocompatibility and enzyme compatibility for biomedical applications. However, leveraging HOFs to create multienzyme cascade antioxidant nanozymes for cerebral ischemia-reperfusion injury (CIRI) therapy remains challenging. Here, selenium-containing nano-HOFs (SeHOFs) were synthesized as glutathione peroxidase mimics, encapsulating superoxide dismutase (SOD) and catalase (CAT) enzymes in situ to form a hybrid cascade antioxidant system (SeHOF@CAT@SOD). SeHOFs exhibited enhanced catalytic activity, preserved enzyme functionality, and provided protection against temperature, proteolysis, and denaturation. The metal-free nanozyme demonstrated excellent biocompatibility and cascade catalytic efficacy, scavenging reactive oxygen species and mitigating apoptosis and ferroptosis in vitro. Peptide modifications enhanced infarct site accumulation, effectively reducing infarct volume, oxidative stress, neuronal apoptosis, ferroptosis, and inflammation in CIRI models. This study underscores the potential of nano-HOFs as scaffolds for advanced therapeutic nanozyme development in ischemic stroke treatment.