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

High Resolution Image Download MS PowerPoint Slide 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 O 2 • –, and degrading H 2 O 2 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.