Diselenide-bridged dual-action nanoscavengers drive fasting-boosted BBB penetration and ROS-responsive resveratrol delivery for synergistic ischemic stroke therapy.

The pathogenesis of ischemic stroke (IS) is critically driven by oxidative stress and the ensuing cytokine storm. While the potent reactive oxygen species (ROS) scavenger resveratrol offers neuroprotection, its targeted delivery across the blood-brain barrier (BBB) remains a substantial challenge. To address this, we developed a BBB-targeting, resveratrol-loaded nanoscavenger (Man@Res@Se-NCP; referred to as M@R@NCP) based on diselenide-bridged nanoscale coordination polymers (NCPs). This system leverages the fasting-induced membrane translocation of GLUT1 to enhance brain accumulation and selectively target ischemic lesions. In the ROS-rich microenvironment characteristic of IS, the diselenide bonds undergo dynamic structural transformations, facilitating synchronized ROS scavenging and controlled release of resveratrol. In murine stroke models, M@R@NCP conferred significant neuroprotection via dual antioxidative and anti-inflammatory mechanisms, including microglial phenotype reprogramming and suppression of neuroinflammatory cascades. This triad of synergistic actions-BBB-traversing delivery via GLUT1-mediated transport, lesion-specific activation through ROS-triggered drug release, and microenvironment remodeling via immunomodulation-enables a therapeutic paradigm shift from broad-scale intervention to precision cerebrovascular therapy. By converging rational nanomedicine design with IS pathophysiology, this study establishes stimuli-responsive nanomaterials as a core strategy for addressing the multifaceted pathology of IS, offering a promising path to improve post-stroke outcomes.