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.