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Controlling wireframe DNA origami nuclease degradation with minor groove binders

By Eike-Christian Wamhoff, Hellen Huang, Benjamin J. Read, Eric Ginsburg, William R Schief, Nicholas Farrell, Darrell J Irvine, Mark Bathe

Posted 27 May 2020
bioRxiv DOI: 10.1101/2020.05.24.110783

DNA nanoparticles have emerged as an intriguing delivery platform as they constitute dynamic, programmable materials that offer unique control over size, shape, and functionalization. However, their utility for therapeutic applications has been limited due to their susceptibility to nuclease degradation. Here, we characterize the stability of algorithmically designed wireframe DNA origami and explore stabilization towards in vivo applications using minor groove binders. Bare 2-helix DNA nanoparticles were found to be stable under typical cell culture conditions, yet they remain susceptible to endonucleases, specifically DNAse I, and degrade rapidly in mouse serum. Restricting minor groove access, specifically with diamidines, resulted in substantial protection against endonucleases. This strategy was found to be compatible with both varying wireframe DNA origami architectures and their functionalization. Our stabilization strategy conveys distinct physicochemical properties compared to established oligo- or polymer-based methods and bears therapeutic potential for minor groove binder delivery to combat infectious diseases and cancer. ### Competing Interest Statement The authors have declared no competing interest.

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