Significance DNA nanotechnology provides a structural toolkit for the fabrication of programmable DNA nano-constructs; however, their use in biomedical applications is challenging due the limited structural integrity in complex biological fluids. Here, we report a class of tailorable molecular coatings, peptoids, which can efficiently stabilize three-dimensional wireframed DNA constructs under a variety of biomedically relevant conditions, including magnesium-ion depletion and presence of degrading nuclease. Furthermore, we show that peptoid-coated DNA constructs offer a controllable anticancer drug release and an ability to display functional biomolecules on the DNA surfaces. Our study demonstrates an approach for building multifunctional and environmentally robust DNA-based molecular structures for nanomedicine and biosensing.