A Dual‐Action Nucleoside‐Based Supramolecular Hydrogel Combats Periodontitis by Disrupting the Bacteria‐Osteoclast Cascade

Periodontitis is a highly prevalent oral inflammatory disease and a recognized risk factor for multiple systemic disorders. 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)-mediated bone resorption, and design a novel self-drug delivery system (APC hydrogel) aiming to break this destructive cycle. This supramolecular hydrogel, constructed from PEGylated, structurally optimized nucleoside derivatives, self-assembles via multivalent hydrogen bonding and demonstrates favorable biocompatibility and metabolic stability in vivo. Functionally, the hydrogel exerts a dual-action 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-protein kinase G (cGMP-PKG) signaling pathway in OC precursors, thereby blocking their differentiation into mature, bone-resorbing cells. This dual-action 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-based supramolecular systems in the treatment of inflammation-associated bone loss.