Gemini Surfactant-Lipid-Based Nanovesicles (“GeminiSomes”) for Oral Delivery of Silybin: A Promising Strategy for Hepatoprotective Therapy

The rising global burden of hepatitis underscores the urgent need for effective liver-targeted therapies. Silybin, a natural flavonolignan from Silybum marianum, is well recognized for its hepatoprotective and antiviral potential but suffers from poor oral bioavailability due to low solubility and rapid metabolism. To address this, we developed a novel surfactant-based nanocarrier system to unlock the therapeutic potential of orally administered silybin. The optimized formulation, comprising biocompatible lipids and cationic surfactants, produced stable nanovesicles (121 nm) with high encapsulation efficiency and biphasic drug release. Caco-2 cell transport studies demonstrated a 4.8-fold enhancement in permeability, while pharmacokinetic analysis revealed a 5.3-fold increase in oral bioavailability. In vivo, the nanoformulation significantly mitigated hepatotoxicity in D-galactosamine- induced hepatitis model, reducing serum ALT, AST, and pro-inflammatory cytokines, while restoring liver architecture. These outcomes were further supported by histological evidence of tissue regeneration. This work introduces a clinically viable nanodelivery strategy that overcomes key biopharmaceutical challenges of silybin, offering a promising translational platform for improving oral hepatitis therapy through enhanced absorption and hepatoprotective efficacy.