Characteristics of Coassembling Nanoparticles Based on Oleanolic Acid and Glycyrrhetinic Acid/Caffeic Acid Phenethyl Ester

Oleanolic acid (OA) is a bioactive natural product with excellent coassembling properties. Glycyrrhetinic acid (GA) and caffeic acid phenethyl ester (CAPE) are natural bioactive molecules with poor water solubility. Herein, we constructed coassembly nanoparticles (NPs) of GA or CAPE with OA through hydrogen bonds and hydrophobic interactions. The resulting OA-GA NPs and OA-CAPE NPs were uniform and spherical, with mass ratios of OA to GA or CAPE in the range of 9:1–5:5. Particle sizes of OA-GA NPs were in the range of 450–550 nm, while those of OA-CAPE NPs were in the range of 500–600 nm, with stronger hydrogen bonding interactions. OA-GA/CAPE NPs had a higher water solubility than their parent molecules. OA-GA/CAPE NPs at a ratio of 8:2 in aqueous solution had the best thermal stability, pH stability, and photostability, with stability retained during 7 days of storage. Coassembly improved the antioxidant properties of OA, GA, and CAPE at mass ratios of 9:1 and 8:2, and OA-CAPE NPs performed better than OA-GA NPs. Meanwhile, compared to free GA or CAPE, the release rates of GA and CAPE have been significantly enhanced after coassembling with OA during simulated gastrointestinal digestion. Furthermore, OA-CAPE NPs at a ratio of 8:2 achieved excellent synergistic enhancement of hepatoprotective bioactivity based on a carbon tetrachloride (CCl4)-induced hepatotoxicity model, performing better than free OA and OA-GA NPs at a ratio of 8:2. This work highlighted the potential for the application of OA in drug delivery, and it provided a complex with high hepatoprotective bioactivity based on naturally occurring active small molecules.