In order to test the effectiveness of nanoparticle- (NP-) loaded bone morphogenetic protein 2 (BMP-2) in chronic osteomyelitis (CO) complicated with bone defect, a new nanodrug delivery system composed of mesoporous silica NP (MSN) and chitosan were used to load BMP-2 and transfer it to the target region. Bone marrow mesenchymal stem cells (BMSCs) were purchased and cultivated to detect the osteogenesis of chitosan-MSN (Chi-MSN) and polylactic acid glycolic acid (PLGA) delivery system. In addition, the osteogenesis of Chi-MSN was further determined by constructing a bone defect mouse model. In physicochemical property test, we found Chi-MSN NPs could effectively maintain stability in vivo and had pH response characteristics. As a result, the release efficiency of dexamethasone (Dex) and BMP-2 in the environment with pH7.4 was less, while it increased significantly in pH 6, so as to reduce the BMP-2 and Dex loss during transportation in vivo. Otherwise, we found that the permeation efficiency of Chi-MSN was significantly higher than that of PLGA delivery system, so as to effectively transport BMP-2 and Dex to action target. In the BMSC test, we found that Chi-MSN could better promote their activity and osteogenesis, and the expression of osteogenesis-related genes (runt-related transcription factor 2 (RUNX-2), osteopontine (OPN), alkaline phosphatase (ALP), and osteopontine (OCN)) in the Chi-MSN group was higher. In the bone defect mouse model test, we also found obviously increased bone trabecula number and thickness by Chi-MSN, contributing to better repair of bone defects. Therefore, BMP-2@Chi-MSN may be a better choice for the therapy of CO complicated with bone defect in the future.