Brain-targeting biomimetic nanozyme enhances neuroprotection in ischemic stroke by remodeling the neurovascular unit.

Dysfunction of the neurovascular unit significantly impacts the prognostic outcomes of ischemic stroke. However, effective strategies to comprehensively modulate the neurovascular unit have yet to be developed. In this work, we introduce a brain-targeting biomimetic nanozyme, A@HPB@THSA, designed to mitigate neurovascular unit dysfunction following ischemia/reperfusion. Specifically, aspirin is encapsulated within a hollow Prussian blue nanozyme, which is subsequently modified with brain-targeting T7 peptide-conjugated human serum albumin, ultimately forming the composite A@HPB@THSA. The overexpression of transferrin receptors on cerebral vascular endothelial cells, along with compromised blood-brain barrier (BBB) permeability, facilitates the accumulation of A@HPB@THSA at cerebral ischemic lesions. The hollow Prussian blue nanozyme component effectively scavenges reactive oxygen species in ischemia/reperfusion-affected brain cells, while the aspirin component inhibits platelet aggregation and neutrophil infiltration, thereby preventing microvascular "no-reflow" and preserving the integrity of the BBB. In rat models of transient middle cerebral artery occlusion, A@HPB@THSA demonstrated comprehensive modulation of the neurovascular unit, including reduced BBB permeability, promoted microglia polarization toward an anti-inflammatory phenotype, and enhanced neuronal survival. This work provides a promising platform to reverse dysfunctional neurovascular unit for ischemic stroke treatment.