Bone-Targeting Selenium-Doped Carbon Dot-Based Nanoparticles for Ferroptosis Suppression and Osteogenesis Against Postmenopausal Osteoporosis.

Ferroptosis plays a critical role in postmenopausal osteoporosis (PMOP) pathogenesis, but targeted therapies remain limited. In this study, we have developed bone-targeting selenium-doped carbon dots conjugated with alendronate (ASCDs) with the dual functionality of suppressing ferroptosis and promoting osteogenesis. In vitro, ASCDs mitigated erastin-induced ferroptosis in osteoblasts and bone-marrow mesenchymal stem cells by activating the system Xc--GSH-GPX4 antioxidant pathway, which reduced lipid peroxidation and restored mitochondrial function. Furthermore, ASCDs induced ALP activation and mineralized nodule formation under ferroptosis conditions, and enhanced expression of osteogenic markers, including RUNX2, OPN, and OSX. In vivo, ASCDs demonstrated superior efficacy compared to non-targeted selenium-doped carbon dots (SCDs), significantly reversing trabecular bone loss in ovariectomized mice, reducing osteoclast activity, and suppressing ferroptosis in bone tissue. Proteomics and biochemical analyses further validated that ASCDs exert therapeutic effects by rescuing GPX4 expression and redox homeostasis. Such dual-functional carbon dots present a targeted strategy to treat PMOP by concurrently inhibiting ferroptosis and restoring bone formation.