Ultrathin 2D Titanium Carbide MXene (Ti3C2Tx) Nanoflakes Activate WNT/HIF‐1α‐Mediated Metabolism Reprogramming for Periodontal Regeneration

Abstract Periodontal defect regeneration in severe periodontitis relies on the differentiation and proliferation of periodontal ligament cells (PDLCs). Recently, an emerging 2D nanomaterial, MXene (Ti 3 C 2 T x ), has gained more and more attention due to the extensive antibacterial and anticancer activity, while its potential biomedical application on tissue regeneration remains unclear. Through a combination of experimental and multiscale simulation schemes, Ti 3 C 2 T x has exhibited satisfactory biocompatibility and induced distinguish osteogenic differentiation of human PDLCs (hPDLCs), with upregulated osteogenesis‐related genes. Ti 3 C 2 T x manages to activate the Wnt/ β ‐catenin signaling pathway by enhancing the Wnt‐Frizzled complex binding, thus stabilizing HIF‐1 α and altering metabolic reprogramming into glycolysis. In vivo, hPDLCs pretreated by Ti 3 C 2 T x display excellent performance in new bone formation and osteoclast inhibition with enhanced RUNX2, HIF‐1 α , and β ‐catenin in an experimental rat model of periodontal fenestration defects, indicating that this material has high efficiency of periodontal regeneration promotion. It is demonstrated in this work that Ti 3 C 2 T x has highly efficient therapeutic effects in osteogenic differentiation and periodontal defect repairment.