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A Biocompatible, Simvastatin-Loaded, Bone-Targeting Lipid Nanocarrier: Breaking the 'Traditional Shackle' to Treat Osteoporosis More Effectively

Most of the previous research on osteoporosis has focused on inhibiting the activity of osteoclasts and not on repairing damaged bone tissue. Recent studies have indicated the potential efficacy of simvastatin (SIM) for osteoporosis. The most important reason to focus on SIM is that it can break the "traditional shackle" of osteoporosis therapy, which has been focused on inhibiting osteoclast activity, and instead treat osteoporosis by promoting osteoblast differentiation and mineralization through the bone morphogenetic proteins (BMP)-Smad signaling pathway, opening up a new avenue for osteoporosis treatment. However, due to poor water solubility, SIM has lower bioavailability, and less bone tissue distribution is observed. Herein, novel lipid nanoparticles (LNPs) delivering SIM (SIM/LNPs) for osteoporosis therapy were developed with aspartic oligopeptide (ASP<sub>n</sub>, here ASP<sub>6</sub>)-based bone-targeting moieties grafted to the nanoparticles (SIM/ASP<sub>6</sub>-LNPs) in an attempt to increase the concentration of SIM in bones with a relatively low dose to minimize adverse effects. In vivo experiments indicated that the ASP<sub>6</sub>-LNPs exhibited ideal bone-targeting characteristics, and in vitro cell evaluation experiments showed LNPs have good biocompatibility with the MC3T3-E1cells. The cell mineralization experiment revealed that the SIM-loaded LNPs induced osteoblast differentiation and the formation of mineralized nodules in MC3T3-E1 cells, achieving the same efficacy as that of SIM. Pharmacodynamic experiments revealed that SIM/ASP<sub>6</sub>-LNPs improved the efficacy of SIM on the recovery of bone mineral density when compared to SIM/LNPs or to SIM alone. Therefore, SIM/ASP<sub>6</sub>-LNPs may represent a potential bone-targeting drug delivery system (DDS) that contributes to the development of a novel osteoporosis treatment.