Mitochondria-Targeted Ferritin Nanozyme Modulates Ros-Pyroptosis Axis In Periodontitis

This study aims to engineer a ferritin nanozyme that targets mitochondrial ROS-pyroptosis axis, thereby addressing the unmet need for precise therapy in periodontitis. A mitochondrial-targeted protein nanoplatform was engineered through rational integration of genetic engineering and protein expression techniques, utilizing modular assembly of three ferritin subunit variants. Platform integrity was confirmed through subsequent characterization, while lysosomal escape capacity and mitochondrial targeting functions were demonstrated in cellular assays. Transcriptome sequencing of healthy and periodontitis gingival tissues identified pyroptosis-related gene expression differences, with orthogonal validation of Transferrin Receptor 1 (TFR1) and pyroptosis protein expression via Western blot. MnO₂ nanozymes were bioengineered through in situ biomineralization within nanocages, and their enzyme-mimicking activities were characterized. The therapeutic mechanism was systematically demonstrated in cellular studies: (1) mitochondrial reactive oxygen species (mtROS) scavenging, (2) restoration of mitochondrial membrane potential, and (3) suppression of caspase-1-dependent pyroptosis. In a murine periodontitis model, pharmacokinetic properties of the platform were evaluated. Immunofluorescence staining and Western blotting assessed ROS scavenging capacity and pyroptosis-associated inflammatory marker expression. The mitochondrial-targeted ferritin nanoplatform achieved lysosomal escape and mitochondrial delivery. Its MnO₂ nanozymes displayed SOD/CAT mimicry, scavenging mtROS, restoring mitochondrial homeostasis, and inhibiting pyroptosis. In periodontitis mice, the platform demonstrated 24-hour retention, attenuated alveolar bone loss, and reduced pyroptosis markers, confirming ROS-pyroptosis coordination. This study pioneers a mitochondria-targeting ferritin nanozyme that coordinately regulates the ROS-pyroptosis axis, providing a breakthrough therapeutic strategy for periodontitis by simultaneously addressing oxidative stress and inflammatory cell death.