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The major therapeutic challenge in periodontitis lies in addressing alveolar bone loss driven by the complex interplay between microbial dysbiosis, immune dysregulation, and bone homeostatic imbalance. Here, we identify a positive feedback loop between periodontal bacteria and osteoclast (OC)\u2010mediated bone resorption, and design a novel self\u2010drug delivery system (APC hydrogel) aiming to break this destructive cycle. This supramolecular hydrogel, constructed from PEGylated, structurally optimized nucleoside derivatives, self\u2010assembles via multivalent hydrogen bonding and demonstrates favorable biocompatibility and metabolic stability in vivo. Functionally, the hydrogel exerts a dual\u2010action by sequentially eradicating key periodontal pathogens and suppressing OC activity. In a ligation model of periodontitis, local application of the hydrogel restored microbial homeostasis and reduced alveolar bone loss by approximately 60%. Mechanistic investigations revealed that APC metabolites activated the cyclic guanosine monophosphate\u2010protein kinase G (cGMP\u2010PKG) signaling pathway in OC precursors, thereby blocking their differentiation into mature, bone\u2010resorbing cells. This dual\u2010action approach effectively disrupts the pathogenic cascade of microbial infection and osteoclastic bone destruction within a single platform, redefining local therapeutic strategies for periodontitis and highlighting the broader potential of nucleoside\u2010based supramolecular systems in the treatment of inflammation\u2010associated bone loss.<\/jats:p>","DOI":"10.1002\/adma.202516181","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T15:11:38Z","timestamp":1766589098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Dual\u2010Action Nucleoside\u2010Based Supramolecular Hydrogel Combats Periodontitis by Disrupting the Bacteria\u2010Osteoclast Cascade"],"prefix":"10.1002","volume":"38","author":[{"given":"Qingxuan","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases Department of Orthodontics West China Hospital of Stomatology Sichuan University  Chengdu Sichuan P. 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