Intrinsically bioactive Zr-MOF nanoparticles modulate the osteoimmune-redox niche to promote periapical bone regeneration

Apical periodontitis remains difficult to repair after intracanal intervention because oxidative stress, immune dysregulation, and impaired bone healing persist within the confined periapical lesion niche. Here, we evaluate an intrinsically bioactive hierarchical mesoporous Zr-MOF nanoplatform, HMUiO-66-NH 2 , as a localized host-modulatory strategy for modulating the osteoimmune-redox microenvironment in apical periodontitis. HMUiO-66-NH 2 exhibits favorable cytocompatibility, efficient cellular internalization, and local retention compatible with intracanal administration. Mechanistically, HMUiO-66-NH 2 is associated with reduced intracellular ROS accumulation and the preservation of the osteogenic competence of bone marrow mesenchymal stem cells, together with a shift in macrophage polarization toward a reparative phenotype and the generation of a macrophage-conditioned milieu associated with enhanced osteogenic responses. In a post-instrumentation rat model of apical periodontitis, local HMUiO-66-NH 2 administration is associated with reduced periapical bone destruction, fewer TRAP-positive osteoclasts, and enhanced bone repair, accompanied by a shift toward reparative macrophage-associated responses. Transcriptomic, protein-level, and inhibitor analyses further identify PI3K-Akt and TGF-β signaling as candidate pathways associated with the macrophage-directed immunoregulatory response. These findings establish a localized dual-action osteoimmune-redox intervention framework for improving bone repair in apical periodontitis after intracanal intervention and support intrinsically bioactive Zr-MOF nanotherapeutics as microenvironment-directed adjuncts in confined inflammatory bone lesions.