An ATP-responsive metal–organic framework against periodontitis via synergistic ion-interference-mediated pyroptosis

ABSTRACT Periodontitis involves hyperactivated stromal cells that recruit immune cells, exacerbating inflammation. This study presents an ATP-responsive metal–organic framework (Mg/Zn-MOF) designed for periodontitis treatment, utilizing ion interference to modulate immune responses and prevent tissue destruction. Addressing the challenges of synergistic ion effects and targeted delivery faced by traditional immunomodulatory nanomaterials, the Mg/Zn-MOF system is activated by extracellular ATP—a pivotal molecule in periodontitis pathology—ensuring targeted ion release. Magnesium and zinc ions released from the framework synergistically inhibit membrane pore formation by attenuating Gasdermin D (GSDMD) expression and activation. This action curtails pyroptosis, lactate dehydrogenase and IL-1β release, thwarting the onset of inflammatory cascades. Mechanistically, Mg/Zn-MOF intervenes in both the NLRP3/Caspase-1/GSDMD and Caspase-11/GSDMD pathways to mitigate pyroptosis. In vivo assessments confirm its effectiveness in diminishing inflammatory cell infiltration and preserving collagen integrity, thereby safeguarding against periodontal tissue damage and bone loss. This investigation highlights the promise of ion-interference strategies in periodontitis immunotherapy, representing a significant stride in developing targeted therapeutic approaches.