Plant‐Derived Extracellular Vesicle‐Like Nanoparticles and Decoction Nanoparticles Exhibit Distinct Therapeutic Effects in Alcoholic Liver Disease via Gut Homeostasis and Macrophage Regulation

Nanoparticles originating from plants have attracted increasing attention owing to the excellent biocompatibility and high potential in disease prevention. Various types of plant-derived nanoparticles have been extensively studied; however, comparative investigations of different nanoparticles originating from the same plant remain limited. In this study, two types of Pueraria lobata-derived nanoparticles-extracellular vesicle-like nanoparticles (PLEVs) and decoction nanoparticles (DE-NPs)-were isolated, and their physicochemical properties and therapeutic activities were systematically compared. PLEVs exhibited superior resistance to digestion and showed extensive distribution to the liver, demonstrating an enhanced ability to overcome the intestinal barrier and reach the liver. In a mouse model of alcoholic liver disease (ALD), PLEVs were internalized by hepatic macrophages, promoting their polarization into anti-inflammatory M2 and scavenging intracellular reactive oxygen species. Although DE-NPs were digested by enzymes in the gastrointestinal tract, they also possessed beneficial effects by maintaining the intestinal barrier integrity and modulating gut microbiota balance. Overall, PLEVs exhibited a superior hepatoprotective effect, which was associated with the restoration of intestinal homeostasis and the attenuation of hepatic inflammation. These findings highlight the distinct delivery pathways and therapeutic mechanisms of the two Pueraria lobata-derived nanoparticles, addressing PLEVs as a promising natural nanomedicine for alleviating liver-related diseases.