Simple one-step synthesis of phosphorylated curcumin as carrier-free bone-targeted nanomedicine: An advanced therapeutic strategy against osteoporosis

Osteoporosis is a metabolic bone disorder characterized by a reduction in bone mass and strength, which in turn leads to an increased likelihood of fracture. Although natural compounds show promising potential for osteoporosis treatment, their performance has been largely restricted by their poor water dispersibility and lack of bone-targeting ability. In this study, curcumin (Cur) was phosphorylated by a facile one-step nucleophilic substitution reaction to create phosphorylated Cur (p-Cur), in which the phenolic hydroxyl groups of Cur were converted to phosphate moieties through reaction with POCl 3 , enabling spontaneous self-assembly of p-Cur into carrier-free nanoparticles (p-Cur NPs) with excellent colloidal stability and bone-targeting ability in aqueous solution. In vitro results revealed p-Cur NPs effectively inhibited osteoclastogenesis in a dose-dependent manner, likely by scavenging reactive oxygen species. Using an ovariectomized murine model, p-Cur NPs demonstrated superior therapeutic outcomes compared to unmodified Cur, particularly in mitigating trabecular bone loss and maintaining skeletal microarchitecture. This phosphorylation-mediated nanonization approach combines simple synthesis with high biosafety, offering a promising paradigm for repurposing hydrophobic natural products into targeted therapeutics for metabolic bone diseases.