Polyphenol-engineered selenium nanocatalysts enable neuroprotective glioblastoma chemoimmunotherapy via nose-to-brain delivery.

Glioblastoma therapy is severely limited by poor blood-brain barrier (BBB) penetration and systemic toxicity of chemotherapeutics. Here, we engineered polyphenol-stabilized selenium nanoparticles (nGPSe NPs, <60 nm) via spatial confinement synthesis as a redox-dual nanocatalytic carrier for afatinib (AFA). These AFA@nGPSe NPs utilize their distinct physicochemical properties to facilitate efficient nose-to-brain delivery, achieving high tumor accumulation while bypassing the BBB. The platform exhibits unique tumor-selective redox duality by generating cytotoxic reactive oxygen species and depleting glutathione within the tumors, yet activating antioxidant defense pathways in normal neural tissues to prevent neurotoxicity. This dual mechanism synergizes with AFA-induced tumor cell death. In orthotopic glioblastoma models, intranasal administration achieved a 60% long-term survival rate, driven by a chemoimmunotherapeutic response involving robust CD8+ T cell and macrophage infiltration. This study presents a multifunctional nanoplatform that integrates tumor microenvironment-responsive catalysis, non-invasive delivery, and immune reprogramming for precise and safe glioblastoma therapy.