Single chiral center epimerization-modulated multi-carrier-free oral hydrogel for remolding inflammatory microenvironment via PI3K/Akt/NF-κB and MAPK signaling pathways

The self-assembly of biomolecules with chiral centers in nature has garnered significant attention due to its biomedical potential. However, how single chiral center epimerization influences molecular co-assembly remains unclear. This study explored natural epimers 18<i>α</i>-glycyrrhizic acid (<i>α</i>-GA) and 18<i>β</i>-glycyrrhizic acid (<i>β</i>-GA), and their co-assembly behaviors with active ingredients pseudoephedrine (PSE), amygdalin (AMY), and magnesium ion (Mg²⁺) of ma-xing-shi-gan-tang (MXSGT). Interestingly, due to hydrogen bonds and coordination bonds, <i>β</i>-GA co-assembled with PSE, AMY, and Mg²⁺ to form nanoparticles in a symmetric staggered manner (<i>β</i>-Quad), appearing as a hydrogel; while <i>α</i>-GA co-assembled with PSE, AMY, and Mg²⁺ to form irregular blocks in a parallel manner (<i>α</i>-Quad), appearing as a precipitation. The distinct assembly mechanism led to variations in microscopic morphology, further resulting in <i>β</i>-Quad's superior cellular uptake efficiency and anti-inflammatory activity compared with <i>α</i>-Quad. Crucially, <i>β</i>-Quad's pH sensitivity and excellent material properties protected active ingredients from gastric acid degradation and enabled controlled release in intestinal, enhancing oral bioavailability. Additionally, <i>β</i>-Quad remolded inflammatory microenvironment via PI3K/Akt/NF-κB and MAPK signaling pathways. This work explored the "Butterfly Effect" induced by single chiral center epimerization during the co-assembly process for the first time, providing a natural and effective solution for oral drug delivery systems.