Rational Design of a Modular Endosomal Escape Platform to Improve Cytosolic Delivery of Nucleic Acids

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NARUM-DISSERTATION-2024.pdf (8.94 MB)
Author(s)
Narum, Steven Michael
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Wallace H. Coulter Department of Biomedical Engineering
The joint Georgia Tech and Emory department was established in 1997
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https://hdl.handle.net/1853/78619
Abstract
Endocytosis has long served as a major bottleneck toward nucleic acid delivery as this class of drugs remain trapped within endosomes. Current research trends to overcome endosomal entrapment provide varied success; however, active delivery agents such as endosomal escape peptides (EEP) have emerged as a prominent strategy to improve cytosolic delivery. Yet, EEPs have poor selectivity between endosomal membranes and cellular membranes, leading to toxicity in clinical trials. Chapter 1 provides a comprehensive overview of the state of nucleic acid drug delivery to highlight key issues that limit human translation. In CHAPTER 2, I characterize and optimize a pH-triggerable trojan horse gene therapeutic that provides a smart ASO release with endosomal acidification and selective membrane disruptive activity. Chapter 3 explores the application of fluorescence lifetime imaging microscopy to study and visualize the subcellular localization and degradation of spherical nucleic acid trafficking. In CHAPTER 4, I develop the foundation for a biocompatible nanoparticle platform that is clinically viable and therapeutically active. Finally, in CHAPTER 5, I summarize the implications of my work and outline exciting topics that should be pursued by future endeavors.
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2024-08-12
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