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

Abstract 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.