Effective repair of bone defects mainly depends on the osteoinductivity and biocompatibility of implants. Herein, we for the first time reported the bioinspired fabrication of carbonated hydroxyapatite/chitosan (CHA/CS) nanohybrid scaffolds using CaCO3/CS porous scaffolds as sacrificial templates, followed by loading TWS119 drugs (CHA/CS/TWS119). After treatment with phosphate buffer solutions, the CaCO3/CS porous scaffolds were in situ converted into CHA/CS nanohybrid scaffolds via the dissolution-precipitation reaction. The as-formed CHA nanoplates with thicknesses of similar to 20 nm and widths of 1.0-2.0 mu m were perpendicular to the scaffold surfaces. The three-dimensional interconnected macropores supported the adhesion and spreading of bone mesenchymal stem cells (BMSCs), and the mesopores within the CHA nanoplates as drug delivery channels improved the drug loading-release properties. The controlled drug release of the CHA/CS/TWS119 nanohybrid scaffolds significantly enhanced the osteogenic differentiation of BMSCs by the activated GSK3 beta/beta-catenin pathway. Moreover, rat cranial defect models revealed the enhancing effects of the CHA/CS/TWS119 scaffold on bone tissue regeneration. The micro-CT, haematoxylin and eosin (H&E) staining, Van Gieson (VG) staining, Masson staining and double fluorochrome labelling results demonstrated that more new bone tissues were formed in the CHA/CS/TWS119 nanohybrid scaffolds than the control group without loading TWS119. Therefore, the CHA/CS/TWS119 nanohybrid scaffold is a promising therapeutic material for bone tissue regeneration.