Self-assembly of phosphorylated dihydromyricetin as a carrier-free bone targeting nanomedicine with enhanced efficacy for osteoporosis treatment

• Phosphorylated dihydromyricetin (p-DMY) was synthesized via a one-step reaction. • p-DMY can self-assemble into bone-targeting nanomedicine. • p-DMY shows high water dispersibility, low toxicity and improved anti-osteoporosis efficacy. • p-DMY exerts its effects via promoting inhibiting osteoclasts. Osteoporosis (OP) is a common metabolic disease, that mainly affects skeletal system with the features, including reduction bone density, deterioration bone structure, bone pain and increase risk of bone fracture. In this work, a well-known anti-osteoporosis natural compound named as dihydromyricetin (DMY) was selected as the model compound to construct a carrier-free bone targeting nanomedicine via a one-step phosphorylation reaction, in which the phenolic groups on DMY were converted into phosphate groups after reacting with phosphorus oxychloride. The resultant phosphorylated DMY (p-DMY) could self-assemble into nanoparticles with excellent water dispersibility and bone targeting capability because of the introduction of hydrophilic phosphate groups. In vitro results demonstrated p-DMY mainly inhibited osteoclast differentiation by blocking NF-κB and MAPK signals in a dose-dependent manner. More interestingly, p-DMY could significantly improve OP treatment efficacy in preventing bone loss and improving the biomechanics of bone tissues as compared with DMY in ovariectomy mice. Therefore, considered the facile synthesis procedure, enhanced OP treatment efficacy as well as negative toxicity of p-DMY, we trust this strategy described in this work should be an elegant tool for construction of natural compounds-based nanomedicines for OP and other metabolic disease treatment.