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.