Transferrin-Enabled Blood-Brain Barrier Crossing Manganese-Based Nanozyme for Rebalancing the Reactive Oxygen Species Level in Ischemic Stroke.

(1) Background: Acute ischemic stroke (IS) is one of the main causes of human disability and death. Therefore, multifunctional nanosystems that effectively cross the blood-brain barrier (BBB) and efficiently eliminate reactive oxygen species (ROS) are urgently needed for comprehensive neuroprotective effects. (2) Methods: We designed a targeted transferrin (Tf)-based manganese dioxide nanozyme (MnO 2 @Tf, MT) using a mild biomimetic mineralization method for rebalancing ROS levels. Furthermore, MT can be efficiently loaded with edaravone (Eda), a clinical neuroprotective agent, to obtain the Eda-MnO 2 @Tf (EMT) nanozyme. (3) Results: The EMT nanozyme not only accumulates in a lesion area and crosses the BBB but also possesses satisfactory biocompatibility and biosafety based on the functional inheritance of Tf. Meanwhile, EMT has intrinsic hydroxyl radical-scavenging ability and superoxide-dismutase-like and catalase-like nanozyme abilities, allowing it to ameliorate ROS-mediated damage and decrease inflammatory factor levels in vivo. Moreover, the released Mn 2+ ions in the weak acid environment of the lesion area can be used for magnetic resonance imaging (MRI) to monitor the treatment process. (4) Conclusions: Our study not only paves a way to engineer alternative targeted ROS scavengers for intensive reperfusion-induced injury in ischemic stroke but also provides new insights into the construction of bioinspired Mn-based nanozymes.