DNA network-encapsulated carnosine/ZnO nano-complexes for enhanced antibacterial efficacy and biocompatibility

Developing localized, smart antibacterial systems is crucial to overcome the limitations of traditional antibiotics. Here, we report the synthesis of a DNase-responsive nano-platform, ZnO@Car@DNA-BAC, using kiwifruit-derived genomic DNA as a sustainable scaffold. The system is engineered by cross-linking DNA with N,N'-Bis(acryloyl)cystamine (BAC) and incorporating L-carnosine (Car) functionalized ZnO nanoparticles (NPs), enabling targeted therapeutic release triggered by bacterial nucleases. Our findings reveal that while nanoparticle surface charge dictates the immediate therapeutic outcome in terms of bacterial membrane affinity, electron paramagnetic resonance (EPR) analysis confirmed ROS-mediated oxidative stress as a secondary killing mechanism. Crucially, the nanocomposite exhibited excellent biocompatibility in 3D spheroid models derived from Raw264.7 and HaCaT cells. The dual-layered encapsulation effectively mitigated the intrinsic toxicity of ZnO NPs, resulting in significantly higher IC₅₀ values and preserved metabolic activity within the 3D micro-tissues compared to bare nanoparticles. Following the tissue-level safety validation, the comprehensive nano-platforms were tested in a C. elegans infection model. The results showed a significant suppression of S. aureus colonization and prolonged host survival, regardless of the initial core charge. This study provides a strategic framework for designing stimuli-responsive, charge-tunable biomaterials for precision infection control, balancing robust antibacterial performance with high tissue-level safety.