Combined strategy of dual-module cerium nanosystem composite extracellular vesicles regulate ROS in the tissue microenvironment to promote periodontitis recovery

ABSTRACT Periodontal disease, a chronic inflammatory condition driven by dysbiotic biofilms and host immune dysregulation, lacks therapeutic strategies that simultaneously eliminate infection, resolve inflammation, and promote tissue regeneration. To bridge this gap, we designed a spatially compartmentalized dual-module nanosystem with ‘‘one cerium, dual functions’’. Specifically, the antibacterial module utilizes hyaluronic acid (HA)-modified single-atom cerium nanozymes (Ce-N-C@HA) delivered to periodontal pockets. Upon HA degradation by bacterial hyaluronidase, the exposed catalytic sites generate hydroxyl radicals (·OH) via peroxidase like (POD-like) activity, enabling targeted pathogen eradication. Concurrently, the immunomodulatory module delivers Lactobacillus reuteri -derived extracellular vesicles (EVs) loaded with ultra-small CeO 2 nanoparticles (CeO 2 -EV) into subgingival tissues. This module efficiently scavenges reactive oxygen species (ROS) and induces macrophage polarization to M2 anti-inflammatory phenotype, significantly alleviating the inflammatory microenvironment. By utilizing cerium's dual functionalities which localized antibacterial action and reconstructs immune homeostasis, this system improves the periodontal microenvironment and promotes tissue regeneration, providing a novel strategy for nanotherapy in oral inflammatory diseases.