Nasal-to-Brain ROS-Responsive Diselenide-Bridged Graphene Nanogel for Targeted Ischemic Stroke Therapy via Microglial Modulation.

Secondary oxidative stress and neuroinflammation following ischemic stroke exacerbate neuronal death, blood-brain barrier (BBB) disruption, and neurological deficits. To address these intertwined injury cascades, we developed a diselenide-bridged hyaluronic acid/graphene oxide quantum dot nanogel (DRC@GOQD-HA-Se) for intranasal delivery of Dauricinea bisbenzylisoquinoline alkaloid with antioxidant and immunomodulatory properties. The diselenide (Se-Se) cross-links confer reactive oxygen species (ROS)-triggered degradation and on-demand drug release, while the HA shell enhances microglial targeting via CD44 receptors and facilitates BBB bypass via nose-to-brain transport.DRC@GOQD-HA-Se directly scavenged multiple ROS, eliminating ∼136 ± 10 U/mL of •OH and ∼80 ± 7 U/mL of O2•-, and degrading H2O2 such that only ∼9% remained (p < 0.001, vs untreated). In a photothrombotic ischemia (PTI) mouse model, intranasal administration reduced infarct size, improved neurological deficit scores by ∼40%, halved the Morris water maze escape latency (≈50% faster learning), and increased locomotor activity by ∼61%. In vitro, the nanogel inhibited M1 microglial polarization, reducing neuronal apoptosis and preserving mitochondrial membrane potential under OGD/R insult. Mechanistically, DRC@GOQD-HA-Se activated the STAT3/iNOS axis, suppressed TLR4/MyD88/NF-κB signaling, and downregulated Bax and cleaved caspase-3. Biodistribution analysis confirmed >5-fold brain accumulation vs free drug, with no systemic toxicity or hemolysis. This multifunctional nanoplatform integrates ROS scavenging, immune modulation, and targeted delivery into a single system, offering a clinically translatable strategy for neuroprotection after ischemic stroke.