Inflamed vessel–anchored release of H 2 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 (H 2 ), we develop an inflamed vessel–targeted/anchored H 2 –producing system by modifying ZrSi 2 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 H 2 via hydrolysis. The released H 2 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/Ca 2+ 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 H 2 release at the BBB interface without requiring nanoparticle intracranial accumulation, this strategy represents a promising and low-burden neuroprotective approach for ischemic stroke.