A natural oleanolic acid self-assembly system for curcumin: Structural insights, enhanced physicochemical properties, and synergistic antioxidant activity

The present study developed a natural nano-assembled delivery system with curcumin (Cur)-synergistic bioactivity using natural oleanolic acid (OA). The OA self-assembled nanoparticles (OA NPs) were systematically prepared via region-limited self-assembly, with their size (20–600 nm) regulated by varying key preparation parameters. The XPS, FTIR, CAT, and MD revealed that the 3-hydroxy oxygen and 17-carboxyl oxygen of OA act as hydrogen bond donor and acceptor, respectively, to form hydrogen bonds. Together with van der Waals forces, these interactions drive the formation of hydrophilic surface-exposed nanoparticles. The OA NPs exhibited good biocompatibility, demonstrated by favorable blood safety (hemolysis rate <5 %) and low cytotoxicity (cell viability >90 %). The Cur was efficiently encapsulated into OA NPs, achieving a LC of 22.81 % and EE of 68.43 %. The encapsulated Cur showed significantly improved physicochemical properties, with a 29.02-fold increase in water solubility, a 3.64-fold enhancement in photostability, and a 2.77-fold improvement in thermal stability compared to free Cur. In vivo , OA NPs exhibited intestinal retention time three times longer than gastric retention, and release studies confirmed their intestinal-selective and sustained-release behavior, which followed the Korsmeyer–Peppas model. The Cur-OA NPs demonstrated optimal antioxidant activity, showing 2.45-fold higher potency (based on EC 50 values) than free Cur, attributable to the synergistic effect between Cur and OA NPs. This study highlights the potential of Cur-OA NPs as an oral antioxidant formulation and offers a promising strategy for developing natural nanocarriers with curcumin-synergistic bioactivity.