Inflamed vessel-anchored release of H2 across the blood-brain barrier for ischemic stroke neuroprotection (PRJCA048931)
Ischemia-reperfusion injury in stroke urgently requires safe and efficient cytoprotection, which is currently unmet by existing drugs. Nanotechnology offers a new promise to enhance drug delivery towards the brain, yet the efficacy of nanomaterials crossing the blood-brain barrier (BBB) is quite limited, and the nanomaterials across the BBB will bring a potential safe risk to the brain parenchyma. Leveraging the neuroprotective and anti-inflammatory effects, strong BBB-crossing ability and high biosafety of hydrogen (H2), we here develop a new kind of inflamed vessel- targeted/anchored H2-producing nanoparticles by modifying ZrSi2 nanoparticles with a P-selectin-binding peptide (ZSNP), mimicking P-selectin/PSGL mediated innate immune recruitment. ZSNP anchored onto the inflamed vasculature in stroke does not need to cross the BBB, avoiding potential safety risks to the brain parenchyma. Instead, it can locally hydrolytically produce H2 that diffuses across the BBB to achieve brain cytoprotection. Unlike conventional drug delivery systems, this design maintains H2 release over 5 days, enabling persistent therapy and avoiding nanoparticle accumulation in the brain parenchyma. Mechanistically, ZSNP orchestrates multicellular recovery processes through H2-mediated redox homeostasis and immunomodulation. Concurrently, ZSNP induces microglia-mediated angiogenesis and neurogenesis, guiding axonal projections along neovascular trajectories and facilitating microglia-neuron crosstalk via the non-canonical Wnt pathway. The resultant neurovascular network reconstruction enables functional neural circuit reintegration, surpassing the therapeutic efficacy of the clinical first-line drug edaravone in structural and functional recovery metrics. The proposed strategy of inflamed vasculature-anchored H2 delivery overcomes current therapeutic limitations, providing a promising ischemic stroke treatment strategy.