DNA Nanostructures: Current Challenges and Opportunities for Cellular Delivery.

DNA nanotechnology has produced a wide range of self-assembled structures, offering unmatched possibilities in terms of structural design. Because of their programmable assembly and precise control of size, shape, and function, DNA particles can be used for numerous biological applications, including imaging, sensing, and drug delivery. While the biocompatibility, programmability, and ease of synthesis of nucleic acids have rapidly made them attractive building blocks, many challenges remain to be addressed before using them in biological conditions. Enzymatic hydrolysis, low cellular uptake, immune cell recognition and degradation, and unclear biodistribution profiles are yet to be solved. Rigorous methodologies are needed to study, understand, and control the fate of self-assembled DNA structures in physiological conditions. In this review, we describe the current challenges faced by the field as well as recent successes, highlighting the potential to solve biology problems or develop smart drug delivery tools. We then propose an outlook to drive the translation of DNA constructs toward preclinical design. We particularly believe that a detailed understanding of the fate of DNA nanostructures within living organisms, achieved through thorough characterization, is the next required step to reach clinical maturity.