Vitamin A-Integrated Cinnamaldehyde Nanoemulsion: A Nanotherapeutic Approach To Counteract Liver Fibrosis via Gut–Liver Axis Modulation

Liver fibrosis, a complex process resulting from most chronic liver diseases, remains devoid of effective treatments. An increasing body of evidence links liver fibrosis to the "gut-liver axis", with disruptions in the gut microbiota-host balance emerging as a critical contributor to its progression. Cinnamaldehyde (Cin), a natural compound with antioxidant, anti-inflammatory, and anticytotoxic properties, has shown potential in counteracting hepatic stellate cell (HSC) activation. Additionally, Cin has been shown to promote probiotics in the intestine, thereby restoring a healthy microbial community. These characteristics position Cin as a promising candidate for liver fibrosis treatment through modulation of the gut-liver axis. In this study, a Vitamin A (Va)-formulated Cin Nanoemulsion (Va-Cin@NM) was developed to enhance the physicochemical stability of Cin while preserving intestinal homeostasis and facilitating targeted liver deposition. In bile duct ligation (BDL)-induced liver fibrosis in rats, Va-Cin@NM intervention significantly reduced bile duct-like structure proliferation and collagen deposition in the liver. These effects are likely attributed to the restoration of gut microbiota, increased short-chain fatty acid (SCFA) concentrations, and improved intestinal integrity. Moreover, Va-Cin@NM treatment suppressed harmful bacterial populations in the liver, thus mitigating immune injury and inflammatory cell recruitment. Consequently, oxidative stress and HSC activation were attenuated. Overall, Va-Cin@NM demonstrates significant potential as a nanotherapeutic approach for liver fibrosis by modulating the gut-liver axis.