Addressing the in vivo delivery of nucleic-acid nanostructure therapeutics

DNA and RNA nanostructures are being investigated as therapeutics, vaccines, and drug delivery systems. These nanostructures can be functionalized with guests ranging from small molecules to proteins with precise spatial and stoichiometric control. This has enabled new strategies to manipulate drug activity and to engineer devices with novel therapeutic functionalities. Although existing studies have offered encouraging in vitro or pre-clinical proof-of-concepts, establishing mechanisms of in vivo delivery is the new frontier for nucleic-acid nanotechnologies. In this review, we first provide a summary of existing literature on the in vivo uses of DNA and RNA nanostructures. Based on their application areas, we discuss current models of nanoparticle delivery, and thereby highlight knowledge gaps on the in vivo interactions of nucleic-acid nanostructures. Finally, we describe techniques and strategies for investigating and engineering these interactions. Together, we propose a framework to establish in vivo design principles and advance the in vivo translation of nucleic-acid nanotechnologies.