A natural polysaccharide scaffold, referred to as "freeze-dry nanogel-crosslinked-porous" (FD-NanoCliP) gel, was tested in comparison with an atelocollagen scaffold with respect to osteogenesis versus the mouse mesenchymal progenitor cell line KUSA-A1. The amphiphilic polysaccharide network, engineered in its structure to fit chemically crosslinked nanogels as building blocks into a physically crosslinked porous gel, revealed a superior osteointegrative performance as compared to the soluble atelocollagen network and a peculiar c-plane orientation growth of apatite crystallites, which resembled the structure of natural enamel. Besides evaluating osteogenesis in the FD-NanoCliP gel scaffold, an additional purpose of this study was to assess its chemical composition at the nanoscale and, through its knowledge, to interpret the osteogenic response of mesenchymal cells. In addition to conventional (optical and electron) microscopy and biological evaluation kits, the peculiar chemistry of the FD-NanoCliP gel scaffold and the formation of apatite on it were characterized by means of several independent analytical probes at the molecular scale, which included Raman, cathodoluminescence, energy dispersive X-ray, and X-ray fluorescence spectroscopies. This body of information consistently provided evidence for a peculiar chemistry developed in osteogenesis at the polysaccharide scaffold surface. Such chemistry is not available in soluble atelocollagen and it is key in the superior bioactivity found in the polysaccharide network.