Aim or purpose: This study develops oxygen-vacancy-engineered CeO₂ nanosheets for synergistic antibacterial/anti-inflammatory periodontitis therapy via ultrasound (US), overcoming limitations of conventional treatments (Hosseini Hooshiar M et al., J Nanobiotechnol 2024;22:207; Kim YG et al., Adv Mater 2024;36:e2210819) Materials and methods: CeO₂ nanosheets were synthesized via hydrothermal reduction and characterized by HRTEM/XPS/EPR. Antimicrobial tests used P. gingivalis (ATCC 33277) and A. actinomycetemcomitans (ATCC 29522) with US (1 MHz, 1.5 W/cm²), assessing ROS generation, live/dead staining, and lipid peroxidation. Antibiofilm effects were evaluated via H₂S scavenging, and macrophage phagocytosis. Twelve-week-old male Sprague-Dawley rats (n=8 per group) were subjected to periodontitis induction through P. gingivalis inoculation combined with ligature placement (Ethics Approval 2023-X19-35). Following 4 weeks of CeO₂ nanosheet treatment, animals underwent comprehensive evaluation including micro-CT analysis, histopathological examination (H&E and Masson staining), and immunohistochemical assessment of IL-6/TNF-α expression. Data were analyzed by ANOVA (p<0.05). Results: US-activated CeO₂ showed 4.2-fold higher ROS production versus controls, eliminating 99.5% pathogens. Biofilm biomass reduced by 92% via combined H₂S depletion. Treatment decreased alveolar bone loss by 48% and inflammatory cytokines by 5.6-fold in vivo. Conclusions: The dual-functional CeO₂ nanosheets represent a breakthrough in periodontitis therapy by synergistically eradicating pathogens and modulating host immunity, offering superior efficacy to conventional approaches.