DNA-based nanotechnology has evolved into an autonomous, highly innovative, and dynamic field of research at the nexus of supramolecular chemistry, nanotechnology, materials science, and biotechnology. DNA-based materials, including origami nanodevices, have started to emerge as an ideal scaffold for use in cellular programming, tissue engineering, and drug delivery applications. We cover herein the applications for DNA as a scaffold for interfacing with, and guiding, the activity of biological systems like cells and tissues. Although DNA is a highly programmable molecular building block, it suffers from a lack of functional capacity for guiding and modulating cells. Coupling DNA to biologically active molecules can bestow bioactivity to these nanodevices. The main goal of such nanodevices is to synthesize systems that can bind to cells and mimic the extracellular environment, and serve as a highly promising toolbox for multiple applications in cellular programming and tissue engineering. DNA-based programmable devices offer a highly promising approach for programming collections of cells, tissue engineering, and regenerative medicine applications.