Oligonucleotides with Modified Backbones as a Strategy to Improve the Delivery of Biomolecules

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Nucleic acid therapeutics and biologics (drugs derived from living organisms) hold transformative potential for the treatment of genetic diseases, where their unmatched selectivity is expected to result in effective therapies for previously unattainable disease targets. However, their translation to the clinic is slowed down by their high molecular weight and hydrophilicity, which prevent them from easily crossing cell membranes to access intracellular targets. As a result, effective and biocompatible delivery strategies are highly sought after to accelerate the development of these drug categories. DNA, as a material, is uniquely placed to address these challenges due to its biocompatibility, automated synthesis, precise base-pairing alphabet, and complete addressability. These properties have given rise to the synthesis of 3D architectures with unmatched precision that show great promise for drug delivery since they can enter cells as opposed to most oligonucleotides. This suggests their 3D organization plays a big role in dictating their biological properties. However, further work is required to ensure nucleic acid nanostructures can access intracellular compartments reliably and unleash their therapeutic potential. Replacing the phosphodiester backbone of DNA is a promising strategy that has the potential to redefine how nucleic acids interact with cells and are internalized. Yet, it has been comparatively unexplored due to synthetic requirements. Consequently, further development of accessible backbone modifications and their incorporation into 3D DNA architectures offers an unparalleled opportunity to simultaneously address a fundamental gap in knowledge in understanding oligonucleotide backbone modifications and to harness their unleveraged potential for the rational delivery of biologics and nucleic acid therapeutics. Towards this, I propose to establish a group that will explore this topic through three specific aims: 1. Backbone modifications to improve the delivery of DNA nanostructures for gene editing 2. Development of self-assembling nucleic acid polyampholytes as a versatile drug delivery platform 3. Protein spherical nucleic acids with matched oligonucleotide shells for the effective delivery of enzyme therapeutics This new knowledge will be transformative in dictating the rational design of oligonucleotide-based drug delivery vehicles and will provide a road map for incorporating backbone modifications into nucleic acid-based nanostructures. Moreover, this research area holds tremendous potential for the successful development of nucleic acid therapeutics and biologics, which require effective and biocompatible delivery strategies to reach their full clinical potential. Further developments in this area will be of tremendous value in the health sector, where the development of effective therapies for cancer and genetic diseases that are highly prevalent in Canada is the limiting step towards improving patient recovery.