<p>Osteoporosis is a metabolic disorder characterized by progressive bone loss, particularly affecting postmenopausal women. Excessive osteoclast activity contributes to bone resorption and skeletal fragility. Celastrol, a natural triterpene, has demonstrated anti-inflammatory and anti-resorptive effects, but its clinical application is limited by poor solubility and systemic toxicity. In this study, we engineered a bone-targeted nano-sustained-release system using mesoporous silica nanoparticles loaded with celastrol. The nanocarrier displayed high bone affinity, sustained drug release, and favorable biocompatibility. In vitro, it suppressed RANKL-induced osteoclast formation and function by downregulating NF-κB and MAPK signaling. In vivo, treatment of ovariectomized rats improved bone mineral density, preserved trabecular microarchitecture, and reduced osteoclast numbers without apparent systemic toxicity. These findings demonstrate that bone-targeted celastrol nanoparticles provide an efficient and safe therapeutic strategy for postmenopausal osteoporosis by inhibiting osteoclastogenesis and protecting bone structure.</p>