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The effect of implantable Zoledronate-PLGA microcapsules (PLGA-ZOL) in periodontitis remains unclear. In this study, we aimed to explore the potential role of PLGA-ZOL in protecting periodontitis and elucidate the underlying mechanism. A rat model of periodontitis was established by ligation the mandibular first molars, then PLGA-ZOL was implanted. The healing volume was scanned by cone-beam computed tomography. Cytokine levels in the gingival tissues were determined by ELISA and RT-PCR. Oxidative stress was indicated by detecting superoxide dismutase concentration and catalase activity. After periodontitis model was successfully established in rats, PLGA-ZOL treatment significantly attenuated alveolar bone loss, as indicated by the increased total healing volume, bone volume/tissue volume and osteoprotegerin level, as well as decreased sRANKL level. PLGA-ZOL treatment also suppressed the inflammatory activities by inhibiting pro-inflammatory cytokine production (TNF-α, IL-1β) but increasing anti-inflammatory cytokine secretion (IL-10). Furthermore, PLGA-ZOL was found to ameliorate oxidative stress in gingival tissues. In conclusion, PLGA-ZOL microcapsules ameliorate alveolar bone loss, gingival inflammation and oxidative stress in an experimental rat model of periodontitis. [ABSTRACT FROM AUTHOR]