Bone morphogenetic protein-2 (BMP-2) is considered one of the most effective and 
extensively used growth factors to induce osteoblast differentiation and 
accelerate bone regeneration. Dexamethasone (Dex) with suitable dosage can 
enhance BMP-2-induced osteoblast differentiation. To strengthen this synergistic 
osteoinductive effect, a pH-responsive chitosan-functionalized mesoporous silica 
nanoparticle (chi-MSN) ensemble was fabricated for dual-delivery of BMP-2 and 
Dex. The MSNs are prepared by a CTAB-templated sol-gel method, and further 
coated by chitosan via the crosslinking of glycidoxypropyltrimethoxysilane 
(GPTMS). The small Dex is encapsulated in the mesopores and the large BMP-2 is 
incorporated into the chitosan coating. These chi-MSNs can quickly release BMP-2 
in a bioactive form and can then be efficiently endocytosed and further realize 
a controlled release of Dex with the decreased pH value into/in cells. With the 
synergistic action of BMP-2 and Dex outside and inside the cell, this dual 
hybrid delivery system can significantly stimulate osteoblast differentiation 
and bone regeneration in vitro and in vivo. Together, this dual-delivery 
strategy for osteogenic protein delivery may enhance clinical outcomes by 
retaining the bioactivity and optimizing the release mode of the drug/protein.