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Currently,major concerns about the safety and efficacy of RNA interference(RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs.Here we screened the aptamer CH6 by cell-SELEX,specifically targeting both rat and human osteoblasts,and then we developed CH6 aptamer-functionalized lipid nanoparticles(LNPs)encapsulating osteogenic pleckstrin homology domain-containing family O member 1(Plekho1)siRNA(CH6-LNPs-siRNA).Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho 1 siRNA,mainly via macropinocytosis,and boosted in vivo osteoblast-specific Plekho1 gene silencing,which promoted bone formation,improved bone microarchitecture,increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents.These results indicate that osteoblast-specific aptamerfunctionalized LNPs could act as a new RNAi-based bone anabolic strategy,advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.