Progress toward Understanding the Interactions between DNA Nanostructures and the Cell

Abstract Advances in DNA nanotechnology empower the programmable assembly of DNA building blocks (oligonucleotides and plasmids) into DNA nanostructures with precise architectural control. As DNA nanostructures are biocompatible and can naturally enter mammalian cells without the aid of transfection agents, they have found numerous biological or biomedical applications as delivery carriers of therapeutic and imaging cargoes into mammalian cells for at least a decade. Nevertheless, mechanistic studies on how DNA nanostructures interact with cells have remained limited and incomprehensive until 2–3 years ago. This Review presents the recent progress in elucidating the “cell–nano” interactions of DNA nanostructures, with an emphasis on three key classes of structures commonly utilized in intracellular applications: tile‐based structures, origami‐based structures, and nanoparticle‐templated structures. Structural parameters of DNA nanostructures and strategies of biochemical modification for promoting intracellular delivery are discussed. Biological mechanisms for cellular uptake, including specific pathways and receptors involved, are outlined. Routes of intracellular trafficking and degradation, together with strategies for re‐directing their trafficking, are delineated. This Review concludes with several aspects of the “bio–nano” interactions of DNA nanostructures that warrant future investigations.