Engineering Smart Bimetallic Ionic-Site MOF Nanozyme Nanocomposites for Microenvironment-Responsive Dynamic Therapy of Periapical Periodontitis

Periapical periodontitis (AP) is an inflammatory disease caused by persistent endodontic biofilms, and its treatment remains challenging because conventional root canal therapy sometimes fails to achieve effective disinfection and tissue regeneration. Herein, a multifunctional bimetallic ion-modified metal-organic framework (MOF) nanozyme composite, MOF-FeAg-AMP@HA, was engineered for synergistic AP therapy. Incorporation of Fe³⁺ and Ag⁺ ions into a UiO-67 MOF scaffold endowed the nanozyme with pH-responsive dual enzymatic activities. Under acidic inflammatory conditions, strong peroxidase (POD)-like activity generated bactericidal hydroxyl radicals (·OH), while under neutral healing conditions, superoxide dismutase (SOD)-like activity scavenged reactive oxygen species (ROS) to alleviate tissue injury. Furthermore, surface functionalization with the antimicrobial peptide LL-37 enhanced bacterial membrane disruption, and a hyaluronic acid (HA) coating improved biocompatibility and stability. The resulting nanocomposite exhibited potent broad-spectrum antibacterial activity and effectively eradicated bacterial biofilms <i>in vitro</i>. Moreover, MOF-FeAg-AMP@HA promoted tissue repair by stimulating endothelial cell migration and angiogenesis. <i>In vivo</i>, using a rat AP model, the nanocomposite suppressed alveolar bone resorption by blocking the NF-κB/HIF-1α/NLRP3 signaling axis to inhibit pyroptosis. Concurrently, it induced macrophage polarization toward the anti-inflammatory M2 phenotype, thereby reprogramming the microenvironment for bone regeneration. This microenvironment-responsive nanoplatform offers a promising strategy for precision therapy of AP by integrating infection control, immune regulation, and tissue regeneration.