Targeted transfection of siRNA to preosteoclasts features the potential of anti-osteoporosis, yet challenge arises from the development of satisfied delivery vehicles. Here, we design a rational core-shell nanoparticle (NP) composed of cationic and responsive core for controlled load and release of small interfering RNA (siRNA) and compatible polyethylene glycol shell modified with alendronate for enhanced circulation and bone-targeted delivery of siRNA. The designed NPs perform well on transfection of an active siRNA (siDcstamp) that interferes Dcstamp mRNA expression, leading to impeded preosteoclast fusion and bone resorption, as well as promoted osteogenesis. In vivo results corroborate the abundant siDcstamp accumulation on bone surfaces and the enhanced trabecular bone mass volume and microstructure in treating osteoporotic OVX mice by rebalancing bone resorption, formation, and vascularization. Our study validates the hypothesis that satisfied transfection of siRNA enables preserved preosteoclasts that regulate bone resorption and formation simultaneously as potential anabolic treatment for osteoporosis.