Chiral-Directed Immunometabolic Reprogramming Promotes Diabetic Wound Healing

This study aimed to determine whether chiral biomaterials could resolve impaired diabetic wound healing by reprogramming immunometabolic crosstalk, providing insights for oral soft tissue repair strategies. Chiral hydrogels incorporating L-/D-configured nanoparticles were applied to full-thickness dorsal wounds in diabetic male db/db mice (12-week-old, n=8/group), approved by Ethics Committee (No.DLASBD0594). RNA sequencing, metabolomics, and multiplex cytokine profiling were performed to decode fibroblast-macrophage dynamics. RT-qPCR and ELISA assessed macrophage polarization (CD206+ M2), while Seahorse analysis quantified mitochondrial metabolism. Statistical significance was determined by ANOVA (p<0.05). L-chiral hydrogels accelerated diabetic wound closure by 40% vs. controls (p<0.01), driving M2 macrophage dominance (2.3-fold increase) and enhancing fibroblast oxidative phosphorylation activity. Mechanistically, L-configuration activated TGF-β/Slug axis, synchronizing anti-inflammatory signaling with metabolic adaptation. Multi-omics results revealed chiral-dependent lipid redistribution, suppressing IL-1β while elevating pro-resolving mediators. Chiral topology orchestrates immunometabolic harmony in diabetic wounds, overcoming persistent inflammation and metabolic stagnation. By mimicking oral mucosal repair mechanisms, this strategy bridges diabetic systemic complications with localized tissue regeneration, offering a blueprint for chiral biomaterial design in oral mucositis and peri-implant soft tissue defects. The findings position chirality as a master regulator of host-material dialogue, with translational potential for diabetes-related oral and systemic wound management.