The ability to modulate stem cell differentiation in a three dimensional (3D) microenvironment for bone tissue engineering in the absence of exogenous pharmaceutical agents such as bone morphogenic protein (BMP-2) remains a challenge. In this study, we introduce extracellular matrix (ECM)-mimicking nanocomposite hydrogels to induce the osteogenic differentiation of human mesenchymal stem cells (hMSCs) for bone regeneration in the absence of any osteoinductive factors. In particular, we have reinforced a photocrosslinkable collagen-based matrix (gelatin methacryloyl, GelMA) using disk-shaped nanosilicates (nSi), a new class of two-dimensional (2D) nanomaterials. We show that nanoengineered hydrogels supported the migration and proliferation of encapsulated hMSCs, with no signs of cell apoptosis or inflammatory cytokine responses. The addition of nSi significantly enhances the osteogenic differentiation of encapsulated hMSCs as evident from the increase in alkaline phosphates (ALP) activity and the deposition of a biomineralized matrix compared to GelMA. We also show that microfabricated nanoengineered microgels can be used to pattern and control cellular behaviour. Furthermore, we demonstrate that nanoengineered hydrogel have high biocompatibility as determined by in vivo experiments using an immunocompetent rat model. Specifically, the hydrogels showed minimum localized immune responses, indicating their ability for tissue engineering applications. Overall, we showed the ability of nanoengineered hydrogels loaded with 2D nanosilicates for the osteogenic differentiation of stem cells in vitro, in the absence of any growth factors such as BMP-2. Our in vivo studies show high biocompatibility of nanocomposites and show the potential for growth factor free bone regeneration.