Optimization of Ellagic Acid-Loaded Liposomes Using Box–Behnken Design and the Modulatory Role of Chitosan Molecular Weight on Their Stability, Digestive Release, and Antioxidant Activity

Ellagic acid (EA) possesses various biological activities, including anti-inflammatory, whitening, and antioxidant properties. Its practical application is limited by poor aqueous solubility and susceptibility to degradation. To overcome these limitations, this study prepared EA liposomes using the thin-film hydration–ultrasonication method, followed by surface modification with low-molecular-weight chitosan (LM-CS) and medium-molecular-weight chitosan (MM-CS), yielding EA liposomes modified with LM-CS (EA-L-LC) and MM-CS (EA-L-MC), respectively. The formulation and preparation process were optimized using a Box–Behnken design combined with response surface methodology. Under optimal conditions, the mean particle size (MPS), polydispersity index (PDI), Zeta-potential, and encapsulation efficiency (EE) of the different liposomes (unmodified EA-L, EA-L-LC, and EA-L-MC) were determined. Morphological observation and functional group characterization were conducted via transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR), respectively. The stability of the various liposomes was compared under different environmental conditions, and their stability and the released amount of EA were evaluated during in vitro digestion. The in vitro antioxidant activity and tyrosinase inhibitory effects of the different liposomes were investigated. After process optimization, the encapsulation efficiency of EA liposomes was effectively enhanced following modification with chitosan of different molecular weights. TEM and FTIR results confirmed that EA was effectively encapsulated, and chitosan was successfully coated onto the outer layer of the liposomes. Compared to unmodified EA liposomes (EA-L), the chitosan-modified liposomes (EA-L-LC and EA-L-MC) exhibited enhanced in vitro antioxidant activity and sustained, slow-release tyrosinase inhibitory effects, along with superior stability across multiple conditions. In vitro digestion experiments demonstrated that EA-L-MC and EA-L-LC achieved slower release rates in simulated gastric fluid compared to EA-L, thereby improving the digestive stability of EA.