Design and fabrication of multifunctional cyanidin-3-O-glucoside-loaded nanonutriosomes with enhanced physicochemical stability and hepatic targeting for mitigating alcoholic liver injury

Alcoholic liver disease (ALD) is one of the most prevalent liver diseases worldwide. There are currently no FDA approved pharmacological therapies specifically designed to prevent or treat ALD. Targeted nutritional interventions offer a promising avenue for ALD management. Cyanidin-3-O-glucoside (C3G), a natural anthocyanin, has shown potential in mitigating alcoholic liver injury, but its therapeutic utility is limited by poor stability and inadequate liver targeting. Here, we report a galactosylated chitosan-modified nanoplatform for the encapsulation and hepatic targeted delivery of C3G. The fabricated nanonutriosomes (C3G@GC-NS) exhibited favorable physicochemical stability, biosafety, and enhanced C3G accumulation in the liver. In a mice model of alcoholic liver injury induced by 15-day ethanol feeding, oral administration of C3G@GC-NS at a dose of 150 mg /kg (C3G equivalent) daily significantly alleviated liver injury. C3G@GC-NS outperformed free C3G in ameliorating steatosis, inflammation, and metabolic dysfunction. Mechanistically, the nanotherapeutic activates the AMPK signaling pathway, regulates PPARα-driven lipid and ethanol metabolism, and restores alcohol-induced gut microbiota dysbiosis. This study presents a rationally designed nanoplatform that enhances the therapeutic efficacy of C3G through coordinated modulation of hepatic metabolism and the gut-liver axis, offering a novel strategy for the treatment of ALD.