Biomimetic Ru‐Mn Nanozyme with Cascade Catalytic Activity Attenuates Secondary Brain Injury in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a lethal stroke subtype with limited treatment options, largely due to secondary injury driven by oxidative stress and neuroinflammation. Here, we developed a ruthenium (Ru)-manganese (Mn) composite nanozyme by integrating Ru nanozyme into Mn-doped zeolitic imidazolate framework (Mn-ZIF) to enable cascade catalytic activity for efficient ROS clearance. In vitro, Ru@Mn-ZIF nanozyme reduced LPS-induced microglia activation and H₂O₂-induced neuronal oxidative damage, showing stronger protective effects than Mn-ZIF nanozyme. In vivo, both intranasal and intravenous administration of Ru@Mn-ZIF nanozyme significantly decreased hematoma volume, preserved blood-brain barrier integrity, suppressed inflammatory responses, and improved neurological recovery in collagenase- and autologous blood-induced ICH models. Biosafety evaluation revealed no pathological or biochemical abnormalities after treatment. These findings highlight Ru@Mn-ZIF nanozyme as a promising therapeutic strategy for mitigating secondary brain injury and improving outcomes after ICH.