Heterochiral DNA Nanotechnology for Biomedical Applications

Author

Tracy L. Mallette, University of New MexicoFollow

Publication Date

Summer 8-1-2023

Abstract

In the past 30 years, there have been major advancements on how to treat and diagnose disease because of the improvement and increase in accessibility of sequencing technology. Nucleic acid-based therapeutics can manipulate protein expression. Likewise, pathogens can be identified and detected with single nucleotide specificity. However, the underlying oligonucleotide technology requires protection against natural defense systems that have evolved to destroy foreign nucleic acids. Many chemical modifications that can protect nucleotides also have significant cytotoxic side effects and must be carefully designed into the strands. A novel way to protect against nuclease-mediated degradation is through the use of mirror-image, left-handed nucleotides which twist to the left, as opposed to the right-handed twist of natural DNA (D-DNA). This enantiomer of natural DNA (L-DNA) is thought to have low cytotoxicity and immunogenicity and have the same hybridization and thermodynamic properties of natural DNA. My thesis is that the combination of heterochiral DNA with dynamic, logic based DNA nanotechnology is a powerful tool for biomedical oligonucleotide development.

In my work, I have developed an interface which can link an L-DNA bioorthogonal computing system to the natural, right-handed world of biology by using heterochiral DNA, DNA containing sections of left- and right-handed chirality in the same strand. My system can translate signals from one chiral domain to another and can be further improved by the addition of L-DNA domains that act as protective caps on D-DNA domains. I establish that the D-DNA components of strand displacement-based molecular circuits constructed using this technique resist degradation during extended incubations in serum-supplemented media and in a living human cell line.

Language

English

Keywords

chirality, molecular computing, DNA strand displacement, biosensing, leak, oligonucleotide therapeutics

Document Type

Dissertation

Degree Name

Biomedical Engineering

Level of Degree

Doctoral

Department Name

Biomedical Engineering

First Committee Member (Chair)

Matthew R. Lakin

Second Committee Member

Diane Lidke

Third Committee Member

Darko Stefanovic

Fourth Committee Member

Chris Thachuk

Recommended Citation

Mallette, Tracy L.. "Heterochiral DNA Nanotechnology for Biomedical Applications." (2023). https://digitalrepository.unm.edu/bme_etds/43