Targeted Inhibition of P. gingivalis OMV-derived TsRNA by tetrahedral framework nucleic acids promotes periodontal regeneration

Outer membrane vesicles (OMVs) derived from Porphyromonas gingivalis (P. gingivalis) exhibit substantially greater pathogenic potential than their parent bacteria, thereby contributing significantly to the pathogenesis of periodontitis. Herein, we investigated the influences of transfer RNA-derived small RNAs (tsRNAs) derived from P. gingivalis on osteogenesis and developed a nanotherapeutic agent to counteract their negative effects. High-throughput tsRNA sequencing and functional analyses identified tRF-Pro-GGG-1 as a key P. gingivalis OMV-derived tsRNA for impairing osteogenesis. Mechanistically, tRF-Pro-GGG-1 directly bound purine-rich element binding protein B (PurB), and inhibited the PurB-mediated transcription of Collagen type I alpha 1 (COL1A1), as shown by ChIP-seq and luciferase assays. To counteract the compromised osteogenesis induced by P. gingivalis-derived OMVs, we engineered a tetrahedral framework nucleic acid (tFNA) functionalized with si-tRF-Pro-GGG-1 (si-tRF-tFNA). This nanotherapeutic agent effectively abrogated OMV-induced osteogenic inhibition by activating PurB and promoted bone regeneration in vitro and in vivo. These findings reveal a novel bacterial RNA-driven pathogenic pathway and provide insights for the development of precise therapeutics for periodontal bone regeneration.