DNA nanotechnology has yielded remarkable advances in composite materials with diverse applications in biomedicine. The specificity and predictability of building 3D structures at the nanometer scale make DNA nanotechnology a promising tool for uses in biosensing, drug delivery, cell modulation, and bioimaging. However, for successful translation of DNA nanostructures to real-world applications, it is crucial to understand how they interact with living cells, and the consequences of such interactions. In this review, we summarize the current state of knowledge on the interactions of DNA nanostructures with cells. We identify key challenges, from a cell biology perspective, that influence progress towards the clinical translation of DNA nanostructures. We close by providing an outlook on what questions must be addressed to accelerate the clinical translation of DNA nanostructures. STATEMENT OF SIGNIFICANCE: Self-assembled DNA nanostructures (DNs) offers unique opportunities to overcome persistent challenges in the nanobiotechnology field. However, the interactions between engineered DNs and living cells are still not well defined. Critical systematization of current cellular models and biological responses triggered by DNs is a crucial foundation for the successful clinical translation of DNA nanostructures. Moreover, such an analysis will identify the pitfalls and challenges that are present in the field, and provide a basis for overcoming those challenges.

Department of Optical and Biophysical Systems Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic

Department of Optical and Biophysical Systems Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic; Institute for Clinical and Experimental Medicine Prague 14021 Czech Republic

Institute for Clinical and Experimental Medicine Prague 14021 Czech Republic

School of Molecular Sciences Arizona State University Tempe AZ 85281 United States; Biodesign Center for Molecular Design and Biomimetics Arizona State University Tempe AZ 85281 United States

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