From stereochemistry to biofunction: epimer-regulated self-assembling galloyl glycoside hydrogels for accelerated wound healing

Although the self-assembly of chiral molecules has been widely studied, the modulation of self-assembly behavior dominated by epimers that differ only in the configuration of a single chiral center remains challenging, especially since research on the biological activity of self-assemblies formed by epimers is not fully explored. Herein, we have synthesized six galloyl glycosides. Their structures differ solely in the configuration of the monosaccharide core, enabling the formation of seven pairs of epimers. Systematic investigation revealed that this stereochemical variation at the sugar scaffold dictates differences in molecular conformation, which in turn leads to distinct intensity of intermolecular hydrogen bonds and π-π stacking, such that only one compound in each pair of epimers can self-assemble to form carrier-free hydrogels. Notably, the configuration of the sugar scaffold not only modulates molecular self-assembly behavior but also exerts profound impacts on biological activity. Among the three galloyl glycosides that can self-assemble to form carrier-free hydrogels, 1,2,3,4,6-penta-O-galloyl-α-D-mannose (α-D-PGMan) demonstrates superior biocompatibility coupled with potent antibacterial efficacy. Meanwhile, it alleviates inflammation and promotes angiogenesis by regulating the phenotype of macrophages, ultimately accelerating wound healing. Therefore, this study reveals the key factors by which epimers regulate the chiral self-assembly behavior, and opens up new avenues for the development of chiral biomedical materials.