Nanoscavenger-enabled clearance of thrombospondin-1 protects the neurovascular unit after cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury (CIRI) is a major cause of secondary brain damage following ischemic stroke, characterized by persistent neurovascular dysfunction and inflammatory amplification. Increasing evidence suggests that extracellular pathogenic proteins released after ischemic insult continue to damage the neurovascular unit during reperfusion; however, most existing therapeutic strategies focus on receptor blockade rather than active elimination of these extracellular mediators. Here, we report an engineered nanoscavenger system designed to selectively intercept and clear thrombospondin-1 (TSP-1), a matricellular protein critically involved in endothelial injury and blood-brain barrier (BBB) disruption after cerebral ischemia-reperfusion. By functionalizing biodegradable nanoparticles with a TSP-1-binding ligand, the nanoscavengers efficiently capture extracellular TSP-1 in ischemic brain tissue, prevent its pathological interaction with endothelial receptors, and promote its systemic redistribution and lysosome-associated processing after macrophage uptake. In murine models of CIRI, nanoscavenger treatment significantly reduced TSP-1 accumulation in the ischemic brain, preserved BBB integrity, and protected the structural and functional integrity of the neurovascular unit. This material-enabled clearance strategy attenuated endothelial apoptosis, suppressed neuroinflammation, and resulted in improved neurological outcomes without inducing systemic toxicity. Collectively, this study demonstrates that nanoscavenger-enabled extracellular protein clearance represents an effective materials-based strategy for mitigating cerebral ischemia-reperfusion injury. These findings highlight the potential of engineered nanomaterials to achieve spatiotemporally controlled elimination of pathogenic extracellular proteins in neurovascular and inflammatory disorders.