The principles of DNA nanotechnology and protein engineering have been combined to generate a new class of artificial extracellular matrices. The potential of this material for ex vivo cellular scaffolding was demonstrated using experiments in which human cervical cancer cells were found to adhere strongly, stay alive, and grow with high migration rates. The use of DNA in our DNA/protein-based matrices makes these structures inherently amenable to structural tunability. By engineering single-stranded domains into the DNA portions, we were able to fine-tune the scaffold's persistence length and stiffness as perceived by cells. This was used to direct the outcome of the cell's cytoskeletal arrangement and overall shape, the status of its signal transduction protein p-FAK, and the localization of its intracellular transcription factors FOXO1a. This contribution lays the groundwork for the facile and modular construction of programmable extracellular matrices that can bring about the systematic study and replication of the naturally occurring extracellular niche.