Construction and Self-Assembly of Oleanolic Acid–Short Peptide Hydrogels Based on Supramolecular Interaction

Oleanolic acid (OA), a natural product with diverse biological activities, faces clinical limitations due to its poor bioavailability caused by hydrophobic pentacyclic structure. To address this issue, we designed a novel class of oleanolic acid–short peptide derivatives (OA-GFFK) by conjugating OA with a water-soluble short peptide (glycine-phenylalanine-phenylalanine-lysine, GFFK). Molecular dynamics simulation (MD) and density functional theory (DFT) predicted its gelation properties, and OA-GFFK was successfully transformed into supramolecular hydrogels via a simple three-step process (dissolution-ultrasonication-resting). Structural characterization revealed that gelation is driven by π–π stacking and hydrogen bonding, leading to a nanofiber network. And the hydrogels exhibited excellent self-healing, shear response, biocompatibility, and antibacterial activity. This study details a research process for the design and simple preparation of oleanolic acid-short peptide derivative hydrogels, providing design insights and a theoretical basis for developing OA derivatives.