Surface Chirality Enables MtlA‐Dependent Antibacterial Activity and Immune Remodeling by Gold Nanoparticles

Skin wound infections persist through a self-reinforcing "infection-inflammation" cycle that compromises tissue repair. Here, we demonstrate that surface chirality of nanomaterials serves as an independent parameter to disrupt this loop through targeted metabolic interference. Using gold nanoparticles (GNPs) as a model, we show that D-chiral GNPs (GNP-D) exhibit superior efficacy over their L-enantiomers (GNP-L) in repressing bacterial basal metabolism and impeding near-surface motility. Integration of transcriptomic profiling and molecular dynamics identifies the mannitol-specific phosphotransferase transporter MtlA as a pivotal target, where GNP-D induces enhanced structural perturbations at functional residues compared to GNP-L. In a murine infection model, GNP-D significantly reduces bacterial burden and accelerates wound closure while repolarizing the wound microenvironment from a persistent pro-inflammatory state toward a pro-resolving and regenerative phenotype. Notably, genetic ablation of mtlA abrogates the chiral bias across all metabolic and immune readouts, providing evidence that this advantage is mediated via the MtlA/PTS axis. These results establish a "chirality-membrane-protein coupling" framework for the rational design of targeted antimicrobial and immunomodulatory nanomedicines.