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Metformin (Met) is recognized for its potent anti\u2010inflammatory properties, yet its limited cellular uptake has hindered its clinical effectiveness in diabetic periodontitis. A tetrahedral framework nucleic acid (tFNA)\u2010based delivery system is developed to enhance Met cellular uptake and investigate its effects on diabetic periodontitis in this study. The tFNA\u2010loaded Met complex (TMC) demonstrates efficient Met loading efficiency and rapid cellular internalization. These results show that in vitro, TMC significantly inhibited pro\u2010inflammatory cytokines and matrix metalloproteinaseat both mRNA and protein levels under high glucose conditions. Mechanistically, TMC suppresses NLRP3\u2010mediated pyroptosis by downregulating NLRP3, Caspase\u20101, Caspase\u201011, and GSDMD, ultimately reducing Mature\u2010IL\u20101\u03b2 and Mature\u2010IL\u201018 production. Furthermore, TMC activates AMPK while inhibiting NF\u2010\u03baB 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\u2010associated inflammation and bone resorption, providing a promising strategy for managing diabetic complications.<\/jats:p>","DOI":"10.1002\/smll.202411740","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T03:47:46Z","timestamp":1737344866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Tetrahedral Framework Nucleic Acid (tFNA)\u2010Loaded Metformin (Met) Modulates Cellular Pyroptosis and AMPK to Ameliorate Type II Diabetic Periodontitis"],"prefix":"10.1002","volume":"21","author":[{"given":"Qi","family":"Han","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases Department of Oral Pathology West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases Department of Oral Pathology West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases Department of Oral Pathology West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirong","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Cai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases Department of Oral Pathology West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-6561","authenticated-orcid":false,"given":"Yunfeng","family":"Lin","sequence":"additional","affiliation":[{"name":"Sichuan Provincial Engineering Research Center of Oral Biomaterials  Chengdu Sichuan 610041 China"},{"name":"National Center for Translational Medicine Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,19]]},"reference":[{"key":"e_1_2_8_1_1","first-page":"34","author":"Bai L.","year":"2024","journal-title":"Adv. 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