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Immunostimulatory Properties of Nucleic Acid Nanoparticles By i Immunostimulatory Properties of Nucleic Acid Nanoparticles by Justin Ross Halman A dissertation submitted to the faculty of The University of North Carolina at Charlotte in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nanoscale Science Charlotte 2020 Approved by: ______________________________ Dr. Kirill Afonin ______________________________ Dr. Kausik Chakrabarti ______________________________ Dr. Ian Marriott ______________________________ Dr. Yuri Nesmelov ______________________________ Dr. Juan Vivero-Escoto ______________________________ Dr. Andy Bobyarchick ii ©2020 Justin Halman ALL RIGHTS RESERVED iii ABSTRACT JUSTIN ROSS HALMAN. Immunostimulatory Properties of Nucleic Acid Nanoparticles. (Under the direction of DR. KIRILL AFONIN) Nucleic acids (DNA and RNA) are ubiquitous biomolecules found throughout all living organisms. They can act as genetic information storage and messengers, enzymes, molecular switches, and much more. Although DNA is used almost exclusively for its ability to store information, discoveries in the roles of RNA in development and homeostasis through complex molecular interactions are ever-expanding. The myriad of roles that nucleic acids can perform makes them ideal therapeutic candidates, as well as molecular machines, and their inherent structure makes investigating their use as materials a worthwhile endeavor. Combining these applications, nucleic acid nanoparticles have the ability to assume any designable structure, varying in shape, size, and composition. This degree of structural customizability, made possible by both Watson-Crick canonical interactions and non-canonical, further enhance the ability to fine-tune a given nanoparticles resulting physicochemical properties. Additionally, their inherent structures make them able to simultaneously carry several different pharmaceuticals including nucleic acid- based agents such as RNA interference inducers, aptamers, and immunostimulatory sequences, as well as small molecules and fluorescent entities. This combination of customizability, biocompatibility, and therapeutic activity makes nucleic acid nanoparticles a highly promising approach for treating complex diseases. Despite rapid advances in the field of therapeutic nucleic acids, unexpected deleterious immune responses have halted both clinical trials and research, leading to hesitation towards their advancement into clinical use. This dissertation aims to elucidate the link between structure and composition of nucleic acid nanoparticles and their ability to produce an immune response in cells. Furthermore, the investigation of chemical modifications, existing both naturally in cells as well as artificially for therapies, is explored for its use in enhancing the stability of nucleic acid nanoparticles while altering their immunostimulatory capabilities. Finally, an approach of dynamic, response activated nucleic acid nanoparticles is explored. iv Acknowledgements There are so many people to thank and acknowledge for their support throughout this PhD process. First and foremost, I would like to thank my advisor, Dr. Kirill Afonin, who taught me so much throughout these years, and provided me a push in the right direction when needed. I’d also like to thank my committee as well as the professors at UNC Charlotte who have helped make me the scientist I am today. Additionally, I would like to thank the members of the Afonin lab, with whom I have spent long hours talking, joking, and occasionally doing research with. Whether through discussions or collaborations, research is very much a team sport and I would be lost without their support. I would also like to thank my family who have supported me far beyond just my years in graduate school. Mom, Dad, and Alexander, everything that I have accomplished thus far has only been made possible with your encouragement, and occasional (and deserved) chastising. Lastly, I need to also thank Morgan Chandler, who falls under both lab mate and family. Thank you for your love and support, spending long hours in lab with me and going on all of our adventures; I can’t wait to see what comes next. v Table of Contents LIST OF TABLES .................................................................................................................................... VII TABLE OF FIGURES ............................................................................................................................ VIII LIST OF ABBREVIATIONS ................................................................................................................. XIV 1 CHAPTER 1: INTRODUCTION ........................................................................................................ 1 1.1 NUCLEIC ACIDS IN MOLECULAR BIOLOGY ........................................................................................ 1 1.1.1 Structure and interactions of nucleic acids .............................................................................. 1 1.1.2 Functions of nucleic acids ....................................................................................................... 4 1.1.3 Chemical modifications of nucleic acids ................................................................................. 8 1.1.4 Natural immune response to nucleic acids ............................................................................ 11 1.2 NUCLEIC ACID THERAPEUTICS ........................................................................................................ 13 1.2.1 Anti-sense oligonucleotides and RNA interference ............................................................... 13 1.2.2 Aptamers as therapeutics ....................................................................................................... 15 1.2.3 Immunostimulation from nucleic acids as a therapeutic approach ........................................ 17 1.3 NUCLEIC ACID NANOTECHNOLOGY ............................................................................................... 18 1.3.1 Rational design and computed assisted strategies ................................................................. 19 1.3.2 Therapeutic nucleic acid nanotechnology.............................................................................. 23 1.3.3 Delivery of therapeutic nucleic acid with nanotechnology .................................................... 25 1.4 DISSERTATION SUMMARY .............................................................................................................. 28 1.5 REFERENCES .................................................................................................................................. 30 2 CHAPTER 2: FUNCTIONALLY-INTERDEPENDENT SHAPE-SWITCHING NANOPARTICLES WITH CONTROLLABLE PROPERTIES ........................................................... 50 2.1 INTRODUCTION ............................................................................................................................... 50 2.2 METHODS ....................................................................................................................................... 52 2.2.1 Nanoparticle assembly and purification. ............................................................................... 52 2.2.2 UV-melting experiments. ...................................................................................................... 53 2.2.3 Kinetics of re-association determination. .............................................................................. 54 2.2.4 Primary human peripheral blood mononuclear cell and whole blood culture for analysis of interferon and cytokine secretion. ......................................................................................................... 55 2.2.5 Nuclease digestion assays. ..................................................................................................... 55 2.2.6 Computational predictions and 3D modeling. ....................................................................... 56 2.2.7 Activation of FRET ............................................................................................................... 57 2.2.8 AFM imaging and sample preparation .................................................................................. 57 2.2.9 Transfection of human cell lines............................................................................................ 58 2.2.10 Fluorescent microscopy ......................................................................................................... 59 2.2.11 Flow Cytometry ..................................................................................................................... 59 2.2.12 Cell proliferation assay .......................................................................................................... 59 2.2.13 Statistics................................................................................................................................. 60 2.3 RESULTS AND DISCUSSION ............................................................................................................. 61 2.3.1 Complementary nanoparticles have controlled rates of re-association and fine-tunable thermodynamic, chemical, and immunogenic properties ...................................................................... 61 2.3.2 Re-association of complementary DNA nanoparticles triggers co-transcriptional formation of RNA nanoparticles ...........................................................................................................................
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