Harnessing Molecular Precision Through DNA Dendrons for Therapeutics and Materials Design

Distler, Max E

doi:https://doi.org/10.21985/n2-hpep-ze89

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Harnessing Molecular Precision Through DNA Dendrons for Therapeutics and Materials Design

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DNA is extremely versatile and powerful, both as a construct in biological applications and as a ligand in materials design due to the fact that its recognition properties can be programmed through sequence and length. Spherical nucleic acids (SNAs), nanoparticles surrounded by a dense shell of DNA or RNA, are a privileged class of structures that have found widespread use in therapeutics, diagnostics, polymer synthesis, and colloidal crystal engineering. These materials, however, are typically limited to isotropic and heterogeneous DNA ligand presentation. Therefore, although SNAs have highlighted the importance of nucleic acid architecture on corresponding properties, it is impossible to use them to probe such relationships at the molecular level. Herein, this thesis describes methods for programming DNA ligand architecture with molecular precision and investigates how this control enables new capabilities in both therapeutics and materials design. Chapter one introduces the role of DNA in nanochemistry, the properties of DNA architectures that have led to significant scientific advances, and the current limitations in controlling DNA presentation at the nanoscale. Chapter two describes the synthesis of a molecularly well-defined DNA dendron and establishes a foundational understanding of how the dendron structure dictates its biological properties. Chapter three investigates the structure-function relationships that impact DNA dendron vaccine function in a molecularly defined manner. In chapter four, the knowledge learned in the previous chapter is used to explore the structure-function relationships of antiviral SNA vaccines in the context of SARS-CoV-2 in humanized mice. Chapter five investigates how DNA dendrons can be utilized in colloidal crystal engineering as foundational building blocks. Specifically, DNA dendrimers of different sizes and valencies are explored as structure-directing agents. Chapter six, investigates a new approach to DNA dendrimer synthesis that enables the encoding of anisotropic orthogonal interactions, allowing for unique structural control over colloidal alloys. Finally, chapter seven provides a summary of the key conclusions drawn and the lessons learned through this research as well as an overview of important future directions. Collectively, these chapters explore how control over DNA architecture at the molecular level can lead to novel and advanced capabilities in the fields of therapeutics and materials design. In biology, it has expanded the foundational understanding of multivalent DNA architectures, while introducing a molecularly defined approach to therapeutics design. In materials, it has led to key insights as to how DNA ligand architecture can be a tool to guide NP assembly, thereby introducing novel structural programmability for the design of modern materials.

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