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Bone morphogenetic protein-2 (BMP-2) is considered as one of the most effective and extensively used growth factor to induce osteoblast differentiation and accelerate bone regeneration. Dexamethasone (Dex) with suitable dosage can enhance the BMP-2-induced osteoblast differentiation. To strengthen this 10 synergistic osteoinductive effect, a pH-responsive chitosan-functionalized mesoporous silica nanoparticles (chi-MSNs) 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 15 bioactive form and then can 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 20 the drug/protein. 65 platform to potentiate the synergistic effect of BMP-2 and Dex.Currently, co-load and co-delivery two or more agents, such as genes, proteins or therapeutic drugs, with complementary or synergistic effect are attracting tremendously interests in nanomedicine to achieve combined therapy. 15 The key for such 70