Engineering Near-Infrared-II Nanoprobes Reveal Dexmedetomidine Potentiating Brain Waste Clearance in Healthy and Sleep-Restricted Mice

The glymphatic system (GS), essential for facilitating the brain's waste removal, is modulated by sleep- and anesthetic drug-induced brain slow oscillation. Dexmedetomidine (Dex), an α2-adrenergic agonist, is a short-term enhancer of slow-wave electroencephalographic and glymphatic influx. However, the potential role of Dex under chronic administration for glymphatic function remains unclear. This study investigates the regulatory effects of long-term Dex administration on GS function by using engineered near-infrared-II (NIR-II) nanoprobes. Three NIR-II probes (BSA@IR-808, IR-808, and IR-808AC) with distinct albumin-binding behaviors were developed to dynamically track GS influx, efflux, and brain parenchyma clearance. NIR-II imaging showed that a low-dose Dex (75 μg/kg) enhanced GS influx without altering physiological parameters. Prolonged administration (5 consecutive days) enhanced cerebrospinal fluid (CSF) influx into the brain parenchyma and accelerated parenchymal clearance of metabolic waste. In a sleep deprivation (SD) model, Dex treatment rescued SD-induced GS dysfunction by increasing nonrapid eye movement sleep duration and recovering CSF influx. Dex treatment increased aquaporin-4 expression and reduced neuroinflammation, thereby recovering SD-associated behavioral impairments. Our study shows that the long-term administration of low-dose Dex enhanced GS function via anesthesia-mediated brain clearance mechanism, suggesting potential therapeutic strategies for neurodegenerative disorders.