Background <p><i>Staphylococcus aureus</i> skin infections represent a persistent clinical challenge owing to their high pathogenicity, multidrug resistance, and biofilm-associated recurrence, which collectively impair antibiotic penetration and exacerbate host inflammation. Emodin, a natural anthraquinone with dual antibacterial and anti-inflammatory activities, has shown therapeutic promise but suffers from poor solubility, rapid clearance, and a lack of pathogen specificity, limiting its translational potential. Here, we developed a multifunctional nanoplatform composed of tetrahedral framework nucleic acids (tFNAs), in which Emodin was noncovalently loaded onto a DNA scaffold to enable sustained release, and a <i>Staphylococcus aureus</i>-specific aptamer was displayed to enable targeted bacterial recognition. Notably, this aptamer-guided design is pathogen oriented, aiming for bacteria-associated enrichment in infected wounds rather than targeting host inflammatory markers or specific immune cell subsets.</p> Results <p>This system markedly potentiated the antibacterial efficacy of Emodin against methicillin-resistant <i>S. aureus</i> (MRSA), significantly inhibited biofilm formation, and disrupted mature biofilms. In murine infection models, the Apt-tFNAs-Emo reduced the bacterial burden, alleviated oxidative stress and TLR4/NF-κB activation, suppressed proinflammatory cytokine production, and accelerated wound healing by restoring collagen deposition and epidermal architecture.</p> Conclusions <p>Overall, this study establishes an aptamer-targeted nucleic acid nanoplatform that integrates antimicrobial delivery, biofilm disruption, and host immunomodulation, offering a promising therapeutic strategy for multidrug-resistant <i>S. aureus</i> skin infections.</p> Graphical abstract <p></p>