Purpose: Locked nucleic acid (LNA)-modified anti-microRNAs have been demonstrated to target mesenchymal stem cells (MSCs) to treat bone diseases. However, the "off-target" effect limits its clinical application. Methods: We selected specific aptamer M4 of MSCs and employed the three-way junction (3WJ) as the core scaffold to construct nanoparticles (3WJ-M4-LNA) for specific delivery of anti-miRNA 138. Results: Our results suggested that the 3WJ-M4-LNA nanoparticles, not 3WJ-M4 or 3WJ-LNA, can specifically deliver anti-miRNA to MSCs, resulting in significant inhibition of miRNA 138 expression. Our experiment further confirmed that the nanoparticles can promote MSCs' osteogenic differentiation by activating the ERK1/2 pathway. In vivo, the nanoparticles promoted bone formation and improved the bone microarchitecture in rabbit osteoporosis models. Conclusions: These results indicate that the 3WJ nanoparticles could develop as a specific therapeutic strategy for osteoporosis.