Intranasal Delivery of an Antioxidant Nanoassembly for Cerebral Ischemia-Reperfusion Injury via Drd2/β-arrestin2/ERK Signaling

Cerebral ischemia-reperfusion injury (CIRI) is caused by reduced cerebral blood flow, leading to excessive oxidative stress and neurological deficits. Curcumin (Cur) is a promising therapeutic agent, but its antioxidant activity is limited by low bioavailability and poor brain penetration. Herein, an intranasal delivery strategy using a tetrahedral framework nucleic acid (tFNAs)-Cur nanoassembly (tFNAs-Cur) was employed for CIRI treatment. tFNAs-Cur was synthesized through self-assembly, achieving a high Cur loading efficiency of 87% and exhibiting potent scavenging activity against reactive oxygen species (ROS) including O2·-, ·OH, and H2O2. In vitro studies showed that tFNAs-Cur inhibited oxygen glucose deprivation/reoxygenation-induced ROS elevation of cytoplasm and mitochondria, and enhanced proliferation and migration of SH-SY5Y cells. In vivo studies demonstrated that intranasal administration of tFNAs-Cur reduced cerebral infarct volume, enhanced neuronal survival, and improved neurological and behavioral outcomes in middle cerebral artery occlusion rats. Further mechanistic investigation using RNA sequencing revealed that tFNAs-Cur exerted its effects by activating the Drd2/β-arrestin2/ERK signaling, thereby improving mitochondrial function and upregulating BDNF levels. Furthermore, hemolysis assays, serum biochemical measurements, and histopathological analyses demonstrated that tFNAs-Cur possessed a favorable biosafety profile both ex vivo and in vivo. This study provides an intranasal antioxidant nanoassembly strategy for CIRI and holds potential for clinical translation.