Inflamed vessel-anchored release of H2 across the blood-brain barrier for ischemic stroke neuroprotection

Ischemic stroke followed by reperfusion urgently requires safe and efficient cytoprotective strategies, a need still unmet by current pharmacotherapies. Nanotechnology holds promise for improved drug delivery to the brain, yet the efficacy of nanomaterials crossing the blood-brain barrier (BBB) is quite limited, and long-term intracranial retention of nanomaterials may provoke neurotoxicity. Leveraging the anti-inflammatory, BBB-crossing, and biosafe properties of hydrogen (H₂), we develop an inflamed vessel-targeted/anchored H₂-producing system by modifying ZrSi₂ nanoparticles with a P-selectin-binding peptide (ZSNP), mimicking P-selectin/P-selectin glycoprotein ligand-mediated innate immune recruitment. Rather than relying on nanoparticle penetration into the brain parenchyma, this design enables ZSNP to anchor at the BBB vasculature, where it locally and continuously generates H₂ via hydrolysis. The released H₂ traverses the BBB, exerting cytoprotection through antioxidant and immunomodulatory mechanisms that coordinate multicellular recovery processes. Furthermore, ZSNP promotes microglia-mediated angiogenesis and neurogenesis, guides axonal projections along neovascular trajectories, and facilitates microglia-neuron interaction via the noncanonical Wnt/CA²⁺ pathway. This reconstruction of the neurovascular network supports the reintegration of functional neural circuits, leading to structural and functional recovery that surpasses the effects of edaravone. By enabling sustained H₂ release at the BBB interface without requiring nanoparticle intracranial accumulation, this strategy represents a promising and low-burden neuroprotective approach for ischemic stroke.