DNA origami protection and molecular interfacing through engineered sequence-defined peptoids

Abstract

DNA nanotechnology has established approaches for designing programmable and precisely controlled nanoscale architectures through specific Watson−Crick base-pairing, molecular plasticity, and intermolecular connectivity. In particular, superior control over DNA origami structures could be beneficial for biomedical applications, including biosensing, in vivo imaging, and drug and gene delivery. However, protecting DNA origami structures in complex biological fluids while preserving their structural characteristics remains a major challenge for enabling these applications. Here, we developed a class of structurally well-defined peptoids to protect DNA origamis in ionic and bioactive conditions and systematically explored the effects of peptoid architecture and sequence dependency on DNA origami stability. The applicability of this approach for drug delivery, bioimaging, and cell targeting was also demonstrated. A series of peptoids (PE1–9) with two types of architectures, termed as “brush” and “block,” were built from positively charged monomers and neutral oligo-ethyleneoxy monomers, where certain designs were found to greatly enhance the stability of DNA origami. Through experimental and molecular dynamics studies, we demonstrated the role of sequence-dependent electrostatic interactions of peptoids with the DNA backbone. We showed that octahedral DNA origamis coated with peptoid (PE2) can be used as carriers for anticancer drug and protein, where the peptoid modulated the rate of drug release and prolonged protein stability against proteolytic hydrolysis. Finally, we synthesized two alkyne-modified peptoids (PE8 and PE9), conjugated with fluorophore and antibody, to make stable DNA origamis with imaging and cell-targeting capabilities. Our results demonstrate an approach toward functional and physiologically stable DNA origami for biomedical applications.

Structural Polymorphism of Single pDNA Condensates Elicited by Cationic Block Polyelectrolytes

“…However, their applications, particularly for biomedical use, have been hampered due to the inherent limitations that DNA origamis require the high content of Mg 2+ ions typically with 10 to 20 mM [107], and moreover, DNA is not stable in physiological environment since it is spontaneously digested by nucleases [108]. To meet these issues, complexation with polycations is shown to be useful [109,110]. It is worthy to note here that complexation may induce collapsing of the origami structures because of the inevitable tendency of condensation and the charge neutralized complexes likely cause inter-origami aggregation as this review dealt with.…”

Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release

“…Its main mechanism of action takes place via type IIA DNA topoisomerase inhibition, but it also affects multiple other cellular processes through DNA intercalation and generation of reactive oxygen species (ROS) (32). The therapeutic potency of various DOX-loaded DNA origami nanostructures (DONs) has been demonstrated using in vitro and in vivo models in a number of reports (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Increasing Complexity in Wireframe DNA Nanostructures

“…This may be extremely interesting in for example sequential release of loaded biomedical cargoes from the DNA vehicles. Nevertheless, there are several ways to increase the overall durability, biocompatibility, and bioavailability of the DNA shapes using protective polymer-, lipid-, protein-and peptoid-coatings [81,[105][106][107][108][109][110][111][112], cross-linking of the DNA strands [113] or the DNA-coating polymers [114]. These methods have often been demonstrated for lattice-based designs, but some of them are equally available for wireframe structures [107].…”