Steven Narum
BME PhD Proposal Presentation

Date: 2023-03-16
Time: 10:00 AM - 12:00 PM
Location / Meeting Link: Emerson 201, https://emory.zoom.us/j/95271620917

Committee Members:
Khalid Salaita, PhD (Advisor); Hanjoong Jo, PhD; Krishnendu Roy, PhD; Yonggang Ke, PhD; Julie Champion, PhD


Title: Rational design of a modular endosomal escape platform to improve cytosolic delivery of nucleic acids

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. A hallmark of the endosome is the acidic environment, which aids in degradation of foreign materials. The long-term goal of this research is to develop nucleic acid strategies that sense and respond to its environment to enable efficient delivery and specific activity for antisense drugs (ASO). Here, I develop a pH-triggered spherical nucleic acid (SNA) that provides a smart ASO release with endosomal acidification and selective membrane disruptive activity. Additionally, current approaches to understand the intracellular trafficking and dissociation of SNAs lack conclusive outcomes. I validate a direct approach by applying fluorescence lifetime imaging microscopy (FLIM) to study the ultimate fate of SNAs. Lastly, as the FDA continues its recent trend of approval for active targeting nucleic acids, I investigate the role of extracellular and intracellular strategies in cancer nanomedicine through the following aims: 1) Characterization and optimization of a pH-triggerable trojan horse gene therapeutic, 2) Exploring the subcellular localization and degradation of spherical nucleic acids using FLIM, and 3) Development of a tissue-specific, biocompatible, and modular nanomedicine to efficiently treat solid tumour cancers.