A carrier-free self-assembled mangiferin hydrogel as a dual-functional oral delivery system for baicalin against acetaminophen-induced acute liver injury.

Baicalin (BAI) is a natural flavonoid with hepatoprotective potential; however, its poor aqueous solubility and low oral bioavailability limit its therapeutic efficacy. Here, a carrier-free, self-assembled mangiferin (MAN) hydrogel was developed for oral BAI delivery without additional polymeric carriers or chemical crosslinkers. The resulting BAI@MAN HG formed a porous network with favorable hydration and viscoelastic properties while retaining antioxidant activity. FTIR, Raman spectroscopy, XRD, and DSC collectively revealed altered molecular organization, reduced crystalline order, and changes in the solid-state environment of BAI following hydrogel formation, consistent with a possible noncovalent association between BAI and MAN. BAI@MAN HG enhanced the apparent solubility, gastrointestinal release, and oral absorption of BAI, resulting in greater systemic exposure than free BAI. In a preventive mouse model of acetaminophen-induced acute liver injury, oral administration of BAI@MAN HG markedly improved liver morphology, reduced hepatocellular damage, normalized serum transaminase levels, and alleviated oxidative stress and inflammation. These protective effects were accompanied by restoration of redox homeostasis and reduced hepatic levels of HMGB1, NF-κB and other inflammatory mediators. Overall, MAN functioned as both a structural gelator and a bioactive matrix, providing a promising carrier-free platform for enhancing the oral delivery and in vivo efficacy of poorly water-soluble bioactives.