Chiral gold nanoparticle synergizes immunometabolic crosstalk and metabolism remodeling for diabetic wound healing.

Abstract

The persistent challenge of diabetic wound healing arises from chronic inflammation, which disrupts the immunometabolic microenvironment. This dysregulated microenvironment exhibits remarkable chirality, but how the stereochemical specificity governs host immunometabolism networks remains elusive. In this study, we engineered chiral gold nanoparticles (L/D-AuNPs) to modulate immunometabolic interactions, thereby significantly promoting diabetic wound healing. To align with the chiral characteristics of the vimentin intermediate filaments (VIFs), L/D-AuNPs with mirror-symmetric windmill-like configurations were synthesized using a seed-mediated growth method. In diabetic murine wounds, L-AuNPs demonstrated superior therapeutic efficacy, enhancing wound healing rate by 29 % compared to the control group. Mechanistic studies revealed that L-AuNPs upregulated the expression of the intermediate filaments vimentin, enhancing fibroblast migration. Concomitant mechanotransduction activated the TGF-β/Slug signaling axis, driving nicotinamide metabolic reprogramming in fibroblasts, which subsequently polarized macrophages toward an anti-inflammatory M2 phenotype. This immunometabolic crosstalk was further validated by single-cell transcriptomic profiling of diabetic patient skin specimens. Based on this finding, we combined L-AuNPs with exogenous nicotinamide, which further accelerated wound regeneration through a significant synergistic effect. This study reveals that chiral AuNPs can promote tissue repair by modulating immunometabolic interactions, providing a novel therapeutic strategy for diabetic wound healing.