A mitochondrial inflammation-oriented nanozyme coordinates dual inflammatory axes to restore alveolar bone homeostasis in periodontitis.

Abstract

Mitochondrial inflammatory stress is an important pathological contributor to alveolar bone loss in periodontitis, yet strategies capable of effectively modulating its initiation and associated signaling network remain limited. Here, a mitochondrial inflammation-oriented nanozyme, CeO₂-DMC@ZIF-8, is rationally designed via in situ integration of the NRF2 agonist DMC into a CeO₂@ZIF-8 framework. This platform combines catalytic ROS scavenging with pH-responsive drug release, enabling integrated modulation of mitochondrial stress-associated inflammatory pathways. Under inflammatory stimulation, CeO₂-DMC@ZIF-8 markedly attenuates mitochondrial ROS accumulation, restores mitochondrial membrane potential, and alleviates endoplasmic reticulum-mitochondria coupling abnormalities. Mechanistically, the nanozyme modulates two key inflammatory pathways, cGAS-STING and NLRP3, thereby suppressing inflammatory amplification and restoring organelle homeostasis. Metabolomic analysis further reveals that lipid mediator remodeling contributes to the attenuation of mitochondrial inflammatory signaling. Functionally, these effects synergistically promote osteogenic differentiation of BMSCs under inflammatory conditions. In a ligature-induced periodontitis model, CeO₂-DMC@ZIF-8 effectively reduces oxidative stress, inhibits osteoclast activity, improves trabecular architecture, and enhances periodontal tissue regeneration. Collectively, this work establishes a nanozyme-based strategy for modulating mitochondrial inflammatory stress, providing a promising approach for restoring bone homeostasis in periodontitis.