Tetrahedral Framework Nucleic Acid (tFNA)‐Loaded Metformin (Met) Modulates Cellular Pyroptosis and AMPK to Ameliorate Type II Diabetic Periodontitis

Abstract Diabetic periodontitis presents a unique therapeutic challenge, primarily due to its chronic inflammatory profile and the associated bone loss driven by immune dysregulation. Metformin (Met) is recognized for its potent anti‐inflammatory properties, yet its limited cellular uptake has hindered its clinical effectiveness in diabetic periodontitis. A tetrahedral framework nucleic acid (tFNA)‐based delivery system is developed to enhance Met cellular uptake and investigate its effects on diabetic periodontitis in this study. The tFNA‐loaded Met complex (TMC) demonstrates efficient Met loading efficiency and rapid cellular internalization. These results show that in vitro, TMC significantly inhibited pro‐inflammatory cytokines and matrix metalloproteinaseat both mRNA and protein levels under high glucose conditions. Mechanistically, TMC suppresses NLRP3‐mediated pyroptosis by downregulating NLRP3, Caspase‐1, Caspase‐11, and GSDMD, ultimately reducing Mature‐IL‐1β and Mature‐IL‐18 production. Furthermore, TMC activates AMPK while inhibiting NF‐κB signaling, thus mitigating the inflammatory response in diabetic periodontitis. In vivo, intraperitoneal administration of TMC in a diabetic periodontitis mouse model significantly reduces inflammatory cell infiltration, collagen degradation, and osteoclast formation, thus alleviating alveolar bone loss. These findings highlight the therapeutic potential of tFNA as an efficient Met delivery vehicle to tackle diabetic periodontitis‐associated inflammation and bone resorption, providing a promising strategy for managing diabetic complications.