Ferumoxytol as a locally injectable nanozyme for Periodontitis: pH-Adaptive catalysis and immunomodulation mechanisms

• FDA-approved Ferumoxytol repurposed as pre-engineered nanozyme platform. . • Injectable depot designed for alkaline periodontal microenvironment targeting. . • SICM reveals nanoscale biophysical immunomodulation at material-biointerface. . • Synergistic biochemical-physical reprogramming suppresses inflammation/bone loss. Periodontitis, a common inflammatory disease, is primarily driven by oxidative stress and aberrant activation of the NF-κB pathway, making effective treatment challenging and necessitating targeted therapies. We repurposed Ferumoxytol, an FDA-approved superparamagnetic iron oxide nanoparticles (SPIONs), as a nanozyme for periodontitis treatment. These SPIONs exhibit pH-adaptive multi-enzyme activities, effectively scavenging reactive oxygen species (ROS) and hydroxyl radicals, with excellent biocompatibility. In a rat periodontitis model, local administration of 15 μg/mL and 15 mg/mL SPIONs reduced inflammation and alveolar bone loss. The treatment restored superoxide dismutase (SOD) activity in serum and gingival tissues, alleviating oxidative stress. Mechanistically, SPIONs suppressed LPS-induced NF-κB activation in RAW 264.7 macrophages, reducing IκBα and p65 phosphorylation. Innovatively, scanning ion conductance microscopy (SICM) revealed nanoscale alterations in macrophage surface topography and electrostatic potential, indicating physical modulation of cell mechanobiology. This study demonstrates SPIONs’ therapeutic efficacy through ROS scavenging, NF-κB suppression, and cell surface modulation, establishing a successful repurposing paradigm for minimally invasive periodontal therapy. This approach reveals a unique immunomodulation mechanism through combined biochemical and biophysical interventions, offering a promising strategy for treating chronic inflammatory diseases and establishing a clinically translatable paradigm: repurposing existing nanodrugs into engineered platforms for precise inflammatory disease therapy.