such as limited bone supply, donor site morbidity, risk of infection, or loss of function. [2,3] Synthetic permanent bone substitution grafts are alternative options, however, those show poor osteointegration, may release toxic ions, and present differences in the mechanical properties at the bone/prosthesis interface that can give rise to ruptures. [1,4] Bone tissue engineering offers an alternative approach, with the potential to repair critical size defects and promote bone regeneration. Although different nanomaterials with osteocompatible, osteoconductive, or osteoinductive effects have been previously described in the literature, [5-8] here we propose an original multifunctional approach based on a hybrid silica nanomaterial that can release calcium and phosphate ions intracellularly, and simultaneously deliver a pro-osteogenic substance, dexamethasone (Dex). We hypothesize that the simultaneous intracellular delivery of different stimuli will result in synergistic effects that allow a scaffold-free strategy to induce the differentiation of stem cells into osteoblasts. Silica nanomaterials (and their degradation products) are biocompatible and "generally recognized as safe" (GRAS) by the U.S. Food and Drug Administration (FDA). [9] The degradation rate of silica nanoparticles depends on their size, porosity, and other parameters, [10] and it has been shown that mesoporous silica nanoparticles (MSNs) with 180 nm diameter degraded over 50% in 3 d, and nearly 100% in 7 d. [11] Large size silicabased bioactive materials have been used in orthopedic applications, [12,13] because they are biocompatible, [14] biodegradable, [15] osteoconductive, [16] and even angiogenic. [13,15] Silica released from these materials, together with calcium and phosphate ions, originate both intracellular and extracellular responses that activate the cells in contact with this stimulus. [15,17,18] Previous studies showed how calcium ions stimulate osteoblast proliferation and differentiation, while phosphate ions enhance the rate of bone matrix production by osteogenic cells. [19,20] This spatiotemporally controlled release also induces the formation of a hydroxyapatite layer, which allows bonding to the bone tissue, hence improving osteointegration. [15,21] This process can be greatly improved by using nanosized bioactive materials, which due to their large specific surface area Bone regeneration requires the presence of specific factors to induce the differentiation of stem cells into osteoblasts. These factors induce osteogenesis by stimulating the expression of bone-related proteins, bone cell proliferation and differentiation. Herein, bioactive mesoporous silica nanoparticles are doped with calcium and phosphate ions while the porous network is loaded with dexamethasone (MSN-CaPDex). The bioactive MSN-CaPDex nanocarriers are prepared without affecting the narrow size distribution, pore structure, and morphology of the MSNs, while incorporating multi-stimuli, complementary ionic/biochemical bioactive mediators. The bioactive nano...