Abstract

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. Graphical abstract