Reversible Protection and Targeted Delivery of DNA Origami with a Disulfide-Containing Cationic Polymer

Sarah Youssef, Emily Tsang, Anirban Samanta, Vipin Kumar, Kurt V Gothelf*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

DNA nanostructures have considerable biomedical potential as intracellular delivery vehicles as they are highly homogeneous and can be functionalized with high spatial resolution. However, challenges like instability under physiological conditions, limited cellular uptake, and lysosomal degradation limit their use. This paper presents a bio-reducible, cationic polymer poly(cystaminebisacrylamide-1,6-diaminohexane) (PCD) as a reversible DNA origami protector. PCD displays a stronger DNA affinity than other cationic polymers. DNA nanostructures with PCD protection are shielded from low salt conditions and DNase I degradation and show a 40-fold increase in cell-association when linked to targeting antibodies. Confocal microscopy reveals a potential secondary cell uptake mechanism, directly delivering the nanostructures to the cytoplasm. Additionally, PCD can be removed by cleaving its backbone disulfides using the intracellular reductant, glutathione. Finally, the application of these constructs is demonstrated for targeted delivery of a cytotoxic agent to cancer cells, which efficiently decreases their viability. The PCD protective agent that is reported here is a simple and efficient method for the stabilization of DNA origami structures. With the ability to deprotect the DNA nanostructures upon entry of the intracellular space, the possibility for the use of DNA origami in pharmaceutical applications is enhanced.

Original languageEnglish
Article number2301058
JournalSmall
Volume20
Issue10
Number of pages12
ISSN1613-6810
DOIs
Publication statusPublished - Mar 2024

Keywords

  • DNA origami
  • antibody
  • bioreducible polymers
  • cationic polymers
  • cell uptake
  • Nanostructures/chemistry
  • DNA/chemistry
  • Disulfides/chemistry
  • Cations/chemistry
  • Nucleic Acid Conformation
  • Polymers/chemistry

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