Oral delivery of Silybin via HA-DOCA-functionalized zein nanocolloids for amelioration of liver fibrosis

Silybin (SIL), a natural flavonoid with recognized anti-hepatic fibrosis activity, suffers from poor aqueous solubility and low oral bioavailability, which restrict its clinical utility. To address these limitations, we developed a novel oral delivery system, termed HDZN/SIL, based on hyaluronic acid–deoxycholic acid (HA–DOCA)-modified zein nanoparticles loaded with SIL. This system was fabricated via an anti-solvent precipitation method. Under optimized conditions, specifically at a zein-to-SIL mass ratio of 10:1, the resulting nanoparticles displayed a uniform spherical morphology with a smooth surface and an average diameter of 127.9 ± 8.2 nm. The formulation also demonstrated high drug loading (97.55 ± 1.02 %) and excellent colloidal stability. Following oral administration, HDZN/SIL achieved effective liver-targeted delivery. In a mouse model of CCl₄-induced hepatic fibrosis, HDZN/SIL treatment resulted in significantly enhanced therapeutic efficacy compared to free SIL, along with an improved safety profile. These findings support HDZN/SIL as a promising strategy to advance the clinical application of SIL.