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Bisphosphonates are used to treat bone diseases such as osteoporosis and cancer-induced bone pain and fractures. It is thought that modifying the pharmacokinetics and biodistribution profiles of bisphosphonates (i.e. rapid renal clearance and extensive bone absorption) will not only reduce their side effects, but also expand their clinical applications to extraskeletal tissues. In the present work, using zoledronic acid (Zol) and calcium as model bisphosphonate and metal molecules, respectively, we prepared DOPA (an anionic lipid)-coated spherical Zol-Ca nanocomposites (Zol-Ca@DOPA) and developed Zol-nanoparticle formulations (i.e. Zol-Ca@bi-lipid NPs) based on the nanocomposites. The influence of the inputted weight ratio of Zol-Ca@DOPA to DSPE-PEG2k on the properties (e.g. size, size distribution, loading efficiency, encapsulation efficiency, zeta potential, and polydispersity) of Zol-Ca@bi-lipid NPs was investigated, and a type of Zol-Ca@bi-lipid NPs with size around 25 nm was selected for further studies. In a mouse model, the Zol-Ca@bi-lipid NPs significantly reduced the bone distribution of Zol, increased the blood circulating time of Zol, and altered the distribution of Zol in major organs, as compared to free Zol. It is expected that similar nanoparticles prepared with bisphosphonate-metal complexes can be explored to expand the applications to bisphosphonates in extraskeletal tissues.