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

Abstract 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.