Disrupting Neutrophil Extracellular Traps with Targeted Cerium Oxide Nanoparticles Ameliorates Diabetic Periodontitis

Diabetic periodontitis (DP) is a prevalent clinical challenge, but the efficacy of available treatments is limited. The pathogenesis of DP is driven by hyperglycemia-induced neutrophil dysregulation, which leads to excessive formation and impaired clearance of neutrophil extracellular traps (NETs), thereby amplifying inflammation and tissue destruction. Cerium oxide nanoparticles (CeNPs) represent a promising therapeutic approach because they mimic multiple enzymes to simultaneously suppress NETosis and facilitate NET degradation. However, the nonspecific effects of unmodified CeNPs within the periodontal niche limit their regulatory precision and therapeutic potential for DP. In this study, we engineered neutrophil-elastase-binding peptide (NEBP)-modified CeNPs (NEBP-PEG-CeNPs) via a DSPE-PEG₂₀₀₀ coating to actively target activated neutrophils. Comprehensive characterization confirmed that this surface modification preserved the multienzyme mimetic activities of CeNPs, enabling the effective regulation of both NET formation and degradation. Using neutrophil models from both human and murine sources, we demonstrated that NEBP conjugation significantly increased cellular internalization by activated neutrophils and potently reduced NETs accumulation under high-glucose conditions. Furthermore, in a DP animal model, NEBP-PEG-CeNPs exhibited superior periodontal tissue preservation and anti-inflammatory effects because of their active targeting capability and increased bioavailability for NET regulation. This study presents a feasible and targeted nanotherapeutic strategy for DP management and provides deep insights into the rational design of CeNPs for the treatment of inflammatory diseases.