Objective To develop an icariside II nanoemulsion (NE-ICS II) to enhance oral bioavailability and improve efficacy against cerebral ischemia-reperfusion injury (CIRI). Methods NE-ICS II was prepared by ultrasonic emulsification and its physicochemical properties were characterized. Pharmacokinetic parameters and brain distribution were systematically evaluated. Therapeutic efficacy was assessed in rats subjected to middle cerebral artery occlusion (MCAO) by measuring infarct volume, neurological deficit scores, and oxidative stress and inflammatory markers. RNA sequencing was performed to elucidate the underlying mechanisms. Results NE-ICS II showed a mean particle size of (147.59 ± 0.71) nm and an encapsulation efficiency of (84.85 ± 5.47) %. NE-ICS II increased the oral bioavailability of ICS II by 2.4-fold and significantly enhanced its accumulation in the brain. Therapeutic oral administration of NE-ICS II markedly improved neurological function, reduced infarct volume, and attenuated oxidative stress and inflammatory responses in MCAO rats. RNA sequencing revealed that NE-ICS II may downregulate signaling pathways associated with oxidative stress and inflammation. Conclusion NE-ICS II substantially improves the oral bioavailability of ICS II and enables effective treatment of CIRI at a low dose, providing a promising strategy for efficient brain delivery of ICS II and for the treatment of central nervous system diseases.

icariside II  /  nanoemulsion  /  cerebral ischemia-reperfusion injury  /  oxidative stress  /  neuroinflammation