Herb-based multicomponent carrier-free hydrogel with antipyretic and anti-inflammatory dual effects by regulating MAPK and NF-κB signaling pathway

Numerous traditional Herbal medicine (THM) formulas have demonstrated their effectiveness during long-term clinical practices worldwide, offering a rich repository for the discovery of new drug and functional biomaterials. Consequently, the development of therapeutic supramolecular hydrogels based on plant-derived bioactive molecules has garnered significant attention in the field of new drug development. In this study, we developed a well-defined orally supramolecular drug derived from the classic Ma-Xing-Shi-Gan decoction (MXSGD) which has been widely used in China for the treatment of COVID-19 symptoms and acute infectious diseases. The four representative chemical components of MXSGD-pseudoephedrine, amygdalin, glycyrrhizic acid, and Ca²⁺-co-assembled into quaternary carrier-free supramolecular structure (Quad hydrogel) through non-covalent interactions. This Quad hydrogel exhibited well thermal reversibility, injectable performance, mechanical strength, sustained release, intestinal retention, enhanced drug absorption, and biocompatibility by oral administration. Moreover, Quad hydrogel significantly inhibited the activation of lipopolysaccharides (LPS)-induced MAPK and NF-κB signaling pathway, thereby synergistically relieving fever in rats more effectively than the original MXSG decoction, equivalent pseudoephedrine (PSE) monomer and the physical mixture four components (Quad mix). In summary, this study provides a novel strategy for developing new supramolecular drug based on classic THM formulas, as well as integrating THM with modern technologies.