Sophorolipid-mediated interfacial modification alters digestion-driven structural evolution of hexosomes and improves baicalin bioaccessibility.

Interfacial properties play an important role in determining the digestion behavior and structural evolution of lipid-based nanocarriers, yet their influence on the gastrointestinal fate of flavonoid glycoside remains incompletely understood. In this study, sophorolipid (SL)-modified inverse hexagonal (HII) hexosomes were developed to investigate how interfacial modification influences the digestion behavior and bioaccessibility of baicalin (BA), a poorly water-soluble flavonoid glycoside selected as a model compound due to its limited aqueous solubility and bioaccessibility. Cryo-TEM and SAXS analyses confirmed that BA was incorporated within a highly ordered inverse hexagonal (HII) lipid architecture, which exhibited particle sizes ranging from 200 to 500 nm with a BA encapsulation efficiency of 94.23 ± 2.53%. SL incorporation affected surface tension, which was associated with changes in lipid hydrolysis behavior and digestion-induced structural evolution. During simulated gastrointestinal digestion, the hexosomal structure remained stable under gastric conditions and underwent structural reorganization in the intestinal phase. As a result, in vitro bioaccessibility of BA increased from 42.85 ± 3.25% to 82.41 ± 6.15% after SL modification (P < 0.0001). Furthermore, fluorescence-based assays suggested differences in cellular interaction and gastrointestinal distribution behavior of SL-modified hexosomes. These findings highlight the importance of interfacial modification in linking interfacial properties with digestion associated structure evolution and provide mechanistic insights for the design of lipid-based systems for improving the gastrointestinal fate of baicalin and related poorly water-soluble bioactive compounds.