DNA framework-based nanomedicine platform: a triple-function strategy for treating periodontitis via antibacterial, anti-inflammatory, and osteogenesis-promoting activities

Abstract Periodontitis is the most prevalent chronic inflammatory condition affecting oral health and is associated with long treatment duration. It is triggered by microbial plaque, which leads to localized and diffuse inflammation, ultimately causing progressive and irreversible damage to the alveolar bone and connective tissue. Therefore, early and effective treatment strategies should prioritize both antimicrobial and anti-inflammatory interventions. Herein, we report a multifunctional DNA nanodrug delivery platform based on tetrahedral framework nucleic acids (tFNAs), which effectively delivers curcumin and defensin to periodontal tissues. This platform exhibits a triple therapeutic effect by eliminating periodontal pathogenic bacteria, reducing inflammatory infiltration in periodontal tissues, and inhibiting bone resorption and degradation. Experimental results showed that curcumin was uniformly loaded onto the framework nucleic acid via groove binding, while defensin was anchored via chemical conjugation, forming the curcumin–defensin–tFNA (Cur-de-tFNA) complex. Due to its structural advantages, this nanodrug platform demonstrates exceptional cellular uptake efficiency and biosafety, significantly enhancing the bioavailability of curcumin and the antimicrobial activity of defensin. Moreover, as the platform degrades into nucleic acids, it presents one of the cleanest nanodrug delivery platforms currently available. As anticipated, the complex demonstrated potent antimicrobial activity, modulated the TLR4 pathway, improved the local microenvironment, promoted the expression of osteogenic proteins, and alleviated local tissue inflammation in a rat model of periodontitis, effectively reducing alveolar bone resorption. We believe that this study offers meaningful insights for multi-targeted combination therapies for periodontitis and provides new directions for the management of bacterial infection-induced local inflammation and bone resorption-related diseases.