Zirconium-Doped Ceria Oxide Nanozymes Alleviate Allergic Rhinitis by Attenuating Oxidative Stress and Stabilizing Mast Cells.

BACKGROUND: Oxidative stress is fundamental to the pathogenesis and progression of allergic rhinitis (AR) during mast cell (MC) degranulation. However, effective therapeutic strategies that target both oxidative stress and the degranulation process remain limited. We developed ultrasmall mPEG (2000)-PE-modified zirconium-doped cerium oxide nanoparticles (PEG-CZ NPs) with broad-spectrum reactive oxygen/nitrogen species (ROS/RNS) scavenging and intrinsic phosphatase-like activity and investigated their prophylactic efficacy in an ovalbumin (OVA)-induced mouse model of AR. METHODS: PEG-CZ NPs were synthesized and characterized, and their superoxide dismutase-, catalase-, and phosphatase-like activities were assessed. Antioxidative and MC-stabilizing effects were examined in anti-DNP IgE-sensitized, DNP-HSA-challenged RBL-2H3 cells by measuring intracellular ROS/RNS, β-hexosaminidase (β-HEX) release, and transcriptomic changes. Prophylactic efficacy and biosafety were evaluated in OVA-induced AR mice following intranasal administration of PEG-CZ NPs (2 mg kg-1). RESULTS: The PEG-CZ NPs were ultrasmall and well dispersed and exhibited robust multienzyme-like activity, efficiently scavenging ROS (H2O2, •OH and O2 •-) and RNS (•NO). At 30 μg mL-1, the PEG-CZ NPs reduced β-HEX release by 50.1% and the intracellular ROS- and RNS-response fluorescence by 84.4% and 95.3%, respectively, without appreciable cytotoxicity. Transcriptomic analysis revealed the suppression of MAPK signaling. In AR mice, they dose-dependently relieved nasal symptoms (maximally 65.7%/79.4% reduction in sneezing/nasal rubbing), rebalanced Th1/Th2 cytokines (48.7% reduction in IL-4, 20.1% reduction in IL-13, 84.7% elevation in IFN-γ), reduced nasal mucosal ROS levels by 69.9% and alleviated mucosal inflammation. No obvious histopathological abnormalities were observed in the major organs during the 31-day study period. CONCLUSION: PEG-CZ NPs alleviated AR by scavenging ROS/RNS and inhibiting MC degranulation. These findings support the use of PEG-CZ nanozymes as a promising prophylactic platform for AR.