Optimizing the Sodium Alginate/Gelatin Ratio Enhances the Stability and Intestinal Delivery of Hesperidin-Loaded Liposomes.

Hesperidin (HES) exhibits limited oral delivery potential because of poor aqueous solubility and low bioaccessibility. Here, HES-loaded liposomes were incorporated into a sodium alginate/gelatin (SA/G) composite hydrogel to construct a liposome-in-hydrogel delivery system. The SA/G ratio was systematically optimized to establish a balanced polymer network through the complementary functions of SA and gelatin. The optimized formulation (H5) exhibited a compact three-dimensional network with cooperative intermolecular interactions, favorable thermal behavior and improved colloidal stability. During simulated gastrointestinal digestion, H5 suppressed premature HES release under oral and gastric conditions while promoting sustained intestinal release. H5 achieved a bioaccessibility of 26.80%, compared with 21.26% for liposomes and 14.26% for free HES, and showed approximately 23-fold and 5-fold higher intestinal tissue-associated accumulation, respectively. These findings indicate that rational optimization of the SA/G network balances matrix integrity, hydration, and liposome stabilization, providing a promising food-grade strategy for controlled gastrointestinal delivery of poorly soluble bioactive compounds.