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 α -glycyrrhizic acid ( α -GA) and 18 β -glycyrrhizic acid ( β -GA), and their co-assembly behaviors with active ingredients pseudoephedrine (PSE), amygdalin (AMY), and magnesium ion (Mg 2+ ) of ma-xing-shi-gan-tang (MXSGT). Interestingly, due to hydrogen bonds and coordination bonds, β -GA co-assembled with PSE, AMY, and Mg 2+ to form nanoparticles in a symmetric staggered manner ( β -Quad), appearing as a hydrogel; while α -GA co-assembled with PSE, AMY, and Mg 2+ to form irregular blocks in a parallel manner ( α -Quad), appearing as a precipitation. The distinct assembly mechanism led to variations in microscopic morphology, further resulting in β -Quad's superior cellular uptake efficiency and anti-inflammatory activity compared with α -Quad. Crucially, β -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, β -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. • The Butterfly Effect of a single chiral center epimerization on co-assembly mechanism, morphology, uptake, and bioactivity. • Distinct assembly mechanisms and morphologies drive β -Quad’s superior uptake and anti-inflammatory efficacy over α -Quad. • β -Quad’s pH responsiveness protects active ingredients from gastric acid degradation, enabling controlled intestinal release. • As the first reported quaternary carrier-free supramolecular hydrogel, β -Quad can remold inflammatory microenvironment.