Title

Combatting Disease via Nanocarrier Targeted Delivery of Therapeutic DNA

Document Type

Article

Major

Chemistry

Mentor

Prof. Jessica Rouge, Dept. of Chemistry

Disciplines

Chemistry

Abstract

Therapeutic nucleic acids (TNAs) have drawn attention in the biomedical world with their capacity to treat previously undruggable hereditary diseases. While a multitude of carrier systems have been able to deliver oligonucleotides, there are still gaps in knowledge regarding the activity of nucleic acid bioconjugates as compared to free oligonucleotides and methods of efficient TNAlocalization to intracellular sites of action. Herein, the design of two types of nucleic acid nanocapsules (NANs) is described for the controlled release of free DNA in the cytosol and the nuclear import of DNA modified with a nuclear localization signal (NLS). Utilizing a biodegradable linker on the outer surface of both NAN constructs, the particles were designed to have the ability to effectively transport DNA across the cell membrane and release carrier-free DNA post-endosomal escape. To test this carrier system for specific localization of nuclear-targeted DNA-peptide bioconjugates, the initial NAN design was further functionalized to incorporate the bioconjugates. Synthesis of several intermediate particle structures for both NAN designs was achieved successfully. Moreover, the conjugation of maleimide-modified DNA to a terminal cysteine thiol of the NLS peptide was visualized using a gel shift assay. So far, results indicate that the conjugation of amine-modified DNA or DNA-peptide conjugate to the carboxy-functionalized nanoparticle core is yet to be optimized. Overall, this work presents the challenge and value in investigating combinations of compatible conjugation chemistries to create a safe and effective carrier for the bioresponsive release of therapeutic cargo.

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