Glucose Epimerization-Modulated Phytochemicals Constructing Carrier-Free Hydrogel for Regulation of Macrophage Phenotype to Promote Wound Healing

The self-assembly of phytochemicals with multiple chiral centers is receiving significant attention for its potential in biomedical applications. However, the impact of single chiral center epimerization on molecular self-assembly remains unexplored. Herein, the self-assembly behavior and bioactivities of 1,2,3,4,6-penta-O-galloyl-alpha-D-glucose (alpha-D-PGG) and 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (beta-D-PGG) is examined, a pair of natural ellagitannins abundant in plants. Interestingly, beta-D-PGG formed a hydrogel without modification, while alpha-D-PGG does not. This occurred due to the balanced distribution of aromatic rings and phenolic hydroxyl groups in beta-D-PGG, facilitating self-assembly via hydrogen bonding and pi-pi stacking into nanofibers. In contrast, alpha-D-PGG's self-assembly is inhibited by steric hindrance. Notably, beta-D-PGG hydrogel demonstrated exceptional antibacterial activity and by regulating macrophage polarization toward the M2 phenotype, thereby reducing inflammation. This study not only reveals the distinct self-assembly behaviors of glucose derivatives but also offers new insights into their potential in biomedical applications, such as wound healing. beta-D-PGG can self-assemble into hydrogels in deionized water without any chemical modification or pretreatment, whereas its epimer alpha-D-PGG does not self-assemble. beta-D-PGG hydrogel not only exhibits great antibacterial activity, anti-inflammatory activity, and promotes wound healing by reducing M1 macrophage expression and increasing M2 macrophage expression, but also exhibits stability, injectability, self-healing, and thermosensitivity, making it potentially an ideal wound dressing. image