A tetrahedral framework nucleic acid-based co-delivery platform enhances the antibacterial activity of nisin and quercetin against MRSA.

The emergence of antibiotic-resistant bacteria necessitates alternative antimicrobial strategies. Here, tetrahedral framework nucleic acids (tFNAs) were engineered as a nanoplatform to co-deliver nisin and quercetin (tFNQ) against a methicillin-resistant Staphylococcus aureus (MRSA) strain isolated from retail pork. tFNAs enhanced bacterial association and enabled nuclease-responsive release, significantly improving antibacterial activity at sub-minimum inhibitory concentrations (sub-MIC) compared with the free combination. tFNQ induced membrane disruption and depolarization, accompanied by reduced hemolytic activity. Transcriptomic profiling and RT-qPCR validation revealed coordinated transcriptional changes in genes associated with virulence regulation and stress response. In particular, agrA was significantly downregulated, whereas the virulence repressor rot was upregulated. These changes were accompanied by reduced expression of hemolysin related genes and genes involved in antimicrobial peptide tolerance. Collectively, these findings demonstrate the advantages of tFNAs as an effective co-delivery platform for enhancing the antibacterial activity of nisin and quercetin against foodborne MRSA. The observed physiological and transcriptomic responses provide molecular evidence associated with the improved antibacterial performance of tFNQ and support the potential application of tFNAs-based co-delivery strategies for antimicrobial intervention.