Ion‐Exchange and Energy‐Stress Strategies Amplified Dual‐Site Nanozyme‐Mediated Ferroptosis/Pyroptosis Inhibition for Neuroprotection

Early neuroprotection is crucial for improving the prognosis of secondary injury after intracerebral hemorrhage (ICH). Herein, this work developed an intelligent blood-brain barrier (BBB)-permeable dual-site nanozyme (TCZM@EcN) prepared by tannic acid (TA) etching to block microglial ferroptosis and pyroptosis for neuroprotection. TCZM@EcN specifically chelated Fe²⁺ in the ICH region through an ion-exchange strategy and obtained higher anti-oxidant property in situ, as well as released Zn²⁺ to upregulate glutathione peroxidase 4 (GPx4) expression for reinforced ferroptosis inhibition. Metformin (Met) hindered fatty acids biosynthesis via an energy-stress strategy, protecting cells from ferroptosis at the source of lipid metabolic pathway. Moreover, ATP inhibition of Met and the chelating nature of TA synergically reduced cell free DNA (cfDNA) content to suppress pyroptosis. Finally, the coating of Escherichia coli Nissle 1917 (EcN)-derived double-layered membrane vesicles (DMVs) with inflammatory inhibitory effect assisted TCZM@EcN hitchhiking neutrophils to cross the BBB and enrich in the ICH region rapidly for more locally efficient oxidative stress reduction and neuroinflammation alleviation. This study confirmed the feasibility and prominent synergistic effects of dual-site nanozyme-induced ion-exchange and energy-stress strategies, which enabled dual inhibition of microglial ferroptosis/pyroptosis for neuroprotection against ICH-induced secondary injury.