In bone research and orthopedics, RNA-interference (RNAi) and nanotechnology can be applied to a vast array of conditions where bone formation needs to be enhanced, providing new options to treat old problems, from osteoporosis and bone tumors to nonunion and critical size defects. The need for new therapeutic tools to improve bone regeneration is evident, mainly in more complex orthopedic surgical procedures. Distraction Osteogenesis (DO) is a unique surgical technique that stimulates bone formation, most frequently used to promote limb lengthening through slow and progressive distraction after osteotomy. The great challenge is to reduce the consolidation phase and prevent the complications related to the maintenance of the external fixator for a long period. Bone Morphogenetic Proteins (BMPs) have been used as potent osteoinductive growth factors, but we considered manipulating the BMP-antagonist NOGGIN through RNA silencing to increase endogenous BMPs levels, as an option for the controversial use of exogenous BMPs. For RNAi-based therapies, the greatest challenge over the past 16 years has been to achieve safe, effective and specific delivery to the target tissue. In vivo studies employed a variety of delivery methods aiming for the ultimate clinical translational application for RNAi technology, but RNAi drugs are still undergoing clinical trials for approval by the US Food and Drug Administration (FDA). This review considers the application of nanotechnology to potentially address the difficulties of delivering silencing RNAs in vivo and in clinical applications, and presents preliminary studies about downregulation of the BMP-antagonist NOGGIN through RNAi in rat bone cells and delivery of siRNA sequences to bone tissue by nanoparticles.