Modular bone tissue engineering is touted as an alternative approach to replace the damaged bone tissue. Hydrogel microcapsules could promote therapeutic properties by providing 3D condition and an increased cell-to-cell interaction. We investigated the osteogenic properties of alginate-nano-silica hydrogels enriched with collagen and gelatin on human osteoblast-like MG-63 cells. For encapsulation, cells were divided into three groups; control (alginate+ nano-silica), collagen (alginate + collagen + nano-silica), and gelatin (alginate + gelatin + nano-silica) and expanded for 28 days. Cell survival was determined by trypan blue staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. To confirm the osteogenic potential, we measured the alkaline phosphatase activity. Alizarin red S staining was used to reveal the existence of hydroxyapatite and transcription BMP-2, osteocalcin and osteonectin evaluated by the real-time polymerase chain reaction. Collagen substrate caused a reduced swelling ratio compared with the control and gelatin groups (P < 0.05). Compared with other groups, collagen had potential to improve mechanical strength and generate porous membrane structure. The addition of collagen (4-fold) and gelatin (1.5-fold) increased cell proliferation rate compared with the control (P < 0.05). Biochemical analysis and Alizarin red S staining showed that collagen-induced osteogenesis by induction of alkaline phosphatase and matrix mineralization. The expression of osteocalcin and BMP-2 was increased in cells from the collagen group. As a result, the combination of natural polymers collagen and gelatin with alginate + nano-silica can increase the osteogenic potential of human osteoblasts.