An Intelligent MXene Nanoplatform for Bone Regeneration in Periodontitis Through Synergistic Scavenging Pathogenic cfDNA and ROS.

Periodontitis, a chronic inflammatory disease driven by bacterial dysbiosis and oxidative stress, remains a major clinical challenge due to its complex pathogenesis and the lack of effective regenerative therapies. Here, we engineer an intelligent pH-responsive MXene-based nanosystem (MPDM) integrating polyethyleneimine (PEI) for pathogen-derived cfDNA capture, methyltransferase-like 3/14 (METTL3/14) for m6A-mediated osteogenic reprogramming, and 2,3-dimethylmaleic anhydride (DMMA) for dynamic charge-shielding to enhance targeting of inflammatory sites targeting. In vitro studies reveal that MPDM exhibits synergistic antibacterial activity, potent reactive oxygen species (ROS) scavenging capacity, and inflammation-triggered payload release. In a murine ligature-induced periodontitis model, micro-CT analysis revealed that MPDM reduced alveolar bone loss and increased the bone volume fraction by 32% (from 53% to 85%) compared to the diseased (Untreated) group. Transcriptomic analysis further reveals that MPDM downregulates toll-like receptor (TLR) and neutrophil extracellular trap (NET) formation signaling pathways, while suppressing osteoclast differentiation. By concurrently neutralizing pathogenic triggers and activating tissue repair, this work establishes a framework for next-generation nanotherapeutics in inflammatory bone disorders, with potential applicability to other multifactorial diseases.