Domino Effect in Epimer Self‐Assembly Induces Diverse Hydrogel Properties for Biomedical Applications

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.