Domino Effect in Epimer Self‐Assembly Induces Diverse Hydrogel Properties for Biomedical Applications
Yihang Zhao, Luping Yang, Zhiwei Wang, Helong Xu, Zhijia Wang, Jihui Lu, Xiang Zhang, Yiqing Huang, Haimin Lei, Xuemei Huang, Penglong WangABSTRACT
Precise regulation of small‐molecule self‐assembly remains a formidable challenge, as subtle structural variations can trigger profound reprogramming of supramolecular architectures. Herein, we demonstrate that C18‐epimerization of glycyrrhizic acid (GA) acts as a molecular switch to modulate both its self‐assembly behavior and the properties of the resulting supramolecular hydrogels. Computational simulations and experimental analyses reveal that this epimer transition induces a “domino effect” that fundamentally rewrites the self‐assembly pathway, particularly by reshaping the intermolecular hydrogen‐bonding (H‐bond) network. Isoglycyrrhizic acid (IGA), the C18‐epimer of GA, forms a densely crosslinked fiber network through a distinct tetramer stacking mode, with significantly enhanced H‐bond interactions arising from altered electrostatic surface potential and molecular planarity. These structural differences yield hydrogels with enhanced injectability and viscosity, supporting the translational potential of IGA‐based hydrogel platforms. Furthermore, IGA co‐assembled with diverse therapeutic agents to form hydrogels that improved drug dispersibility and produced enhanced therapeutic effects in the evaluated preclinical models. This study elucidates the epimer‐governed cascade from molecular stereochemistry to macroscopic function and establishes a stereochemical strategy for engineering supramolecular biomaterials.