The chemical functionalization of nanomaterials with bioactive molecules has been used as an effective tool to mimic extracellular matrix (ECM) and to study the cell-material interaction in tissue engineering applications. In this respect, this study demonstrates the use of enantiomerically functionalized periodic mesoporous organosilicas (PMO) for the generation of new multifunctional 3D nanocomposite (NC) hydrogels to control the affinity of cells to the hydrogel surfaces and so to control the enrichment of cells and simultaneous drug delivery in 3D network. The functionalization of PMO with enantiomers of bioactive molecules, preparation of their nanocomposite hydrogels, and the stereoselective interaction of them with selected cell types are described. The results show that the affinity of cells to the respective NC hydrogel scaffolds is affected by the nature of the biomolecule and its enantiomers, which is more pronounced in serum containing media. The differentiation of enantiomorphous NC hydrogels by cells is used to enrich one cell type from a mixture of two cells. Finally, PMO are utilized as nanocontainers to release two different dye molecules as, a proof of principle for multidrug delivery in 3D NC hydrogel scaffolds.