Hijacking of Bacterial ABC Transporters by DNA Nanodelivery System to Achieve Synergistic Antibacterial and Tissue Repair

ABSTRACT Antimicrobial resistance (AMR) poses a growing global health threat, particularly for soft tissue and wound infections caused by multidrug‐resistant pathogens. Bacterial adenosine triphosphate (ATP)‐binding cassette (ABC) transporters are essential for antibiotic efflux and nutrient uptake and offer a unique opportunity to convert innate microbial defenses into targeted therapeutic entry routes. Here, we report a size‐controlled dumbbell‐shaped DNA nanostructure functionalized with glucose polymers, biotinylated photosensitizers, and L‐arginine as a nutrient‐mimicking nanodelivery platform that hijacks bacterial ABC transporters. The ultrasmall DNA dumbbell and glucose polymer coating promoted efficient transporter‐mediated internalization, enabling spatially confined photothermal/photodynamic antibacterial activity. Simultaneously, the heat‐induced depolymerization of the DNA scaffold triggered L‐arginine release and nitric oxide production, accelerating fibroblast migration and angiogenesis via the NO/cGMP/PKG pathway to enhance tissue repair. This system exhibited efficient bacterial targeting and potent bactericidal effects in vitro. In wound models inoculated with both MRSA and MDR‐PA, it significantly reduced the bacterial burden, increased collagen deposition, and promoted rapid wound healing without detectable toxicity. Overall, this strategy repurposes bacterial physiological defenses as therapeutic conduits and provides a versatile approach for the precise treatment of AMR‐associated infections.