Title:
Development of microRNA triggered therapeutic oligonucleotides and gold nanoparticle conjugates to improve specificity of RNA therapeutics
Development of microRNA triggered therapeutic oligonucleotides and gold nanoparticle conjugates to improve specificity of RNA therapeutics
| dc.contributor.advisor | Salaita, Khalid | |
| dc.contributor.advisor | Jo, Hanjoong | |
| dc.contributor.author | Zhang, Jiahui | |
| dc.contributor.committeeMember | Kwong, Gabe | |
| dc.contributor.committeeMember | Roy, Krishnendy | |
| dc.contributor.committeeMember | Xia, Younan | |
| dc.contributor.committeeMember | Wongtrakool, Cherry | |
| dc.contributor.department | Biomedical Engineering (Joint GT/Emory Department) | |
| dc.date.accessioned | 2022-01-14T16:03:10Z | |
| dc.date.available | 2022-01-14T16:03:10Z | |
| dc.date.created | 2020-12 | |
| dc.date.issued | 2020-12-07 | |
| dc.date.submitted | December 2020 | |
| dc.date.updated | 2022-01-14T16:03:10Z | |
| dc.description.abstract | RNA-targeting oligonucleotide therapeutics and their nanoparticle conjugates hold great promise in treating intractable diseases, but their clinical applications are still limited by significant barriers including the lack of tissue or cell type specificity. Current strategy to improve tissue or cell type specificity of oligonucleotides therapeutics mainly involves conjugation with ligands. However, this strategy encounters bottleneck in diseased conditions where a specific surface marker is absent. In addition to protein markers, transcriptomic techniques have revealed complex and diverse alterations of coding and non-coding transcripts in different tissues, cell types or disease conditions, which opens up opportunities to control the activity of oligonucleotide therapeutics utilizing these endogenous transcripts to improve their specificity. The overall hypothesis of the dissertation is that using specific transcripts as triggering stimulus, oligonucleotides and their nanoparticle conjugates can be activated via toehold-mediated strand displacement reaction to conditionally regulate gene expression. As a proof-of-concept, we chose miRNA as the transcript trigger, hoping to provide a foundation for future design of smart therapeutics sensing more complicated transcript inputs. In this dissertation, we demonstrated the idea of miRNA-inducible conditional gene regulation agents with two models: (1) miR-33 triggered activation of DNAzyme-gold nanoparticle (AuNP) conjugates to down regulate tumor necrosis factor α (TNFα) in pro-inflammatory macrophages; and (2) miR-122-indicible antisense to down regulate hypoxia inducible factor 1α (HIF1α) in liver cells. In addition, to gain insights on the intracellular fate of oligonucleotide-AuNP conjugates for better design of conditional gene regulatory agents, we leveraged a powerful imaging modality, fluorescence lifetime imaging (FLIM), to monitor the intracellular integrity of oligonucleotide-AuNP conjugates. Programmable therapeutics with controllability of location, timing and intensity of their activity can lead to precise medicine with minimal side effects. We envision that the design principles for conditional oligonucleotides and their AuNP conjugates discovered from this dissertation could be adopted to a variety of translatable clinical applications and improve the controllability and safety of oligonucleotide therapeutics and nanoparticle conjugates. | |
| dc.description.degree | Ph.D. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/1853/65989 | |
| dc.language.iso | en_US | |
| dc.publisher | Georgia Institute of Technology | |
| dc.subject | RNA therapeutics | |
| dc.subject | DNAzyme | |
| dc.subject | Antisense oligonucleotide | |
| dc.subject | Gold nanoparticle | |
| dc.subject | Gene regulation | |
| dc.subject | miRNA | |
| dc.subject | Toehold-mediated strand displacement | |
| dc.subject | Specificity | |
| dc.title | Development of microRNA triggered therapeutic oligonucleotides and gold nanoparticle conjugates to improve specificity of RNA therapeutics | |
| dc.type | Text | |
| dc.type.genre | Dissertation | |
| dspace.entity.type | Publication | |
| local.contributor.advisor | Jo, Hanjoong | |
| local.contributor.advisor | Salaita, Khalid | |
| local.contributor.corporatename | Wallace H. Coulter Department of Biomedical Engineering | |
| local.contributor.corporatename | College of Engineering | |
| relation.isAdvisorOfPublication | 7eb8fb49-de34-4fc6-aea8-80b31a2a2be8 | |
| relation.isAdvisorOfPublication | 473078da-e893-44af-8f0f-7a8cda93d9f5 | |
| relation.isOrgUnitOfPublication | da59be3c-3d0a-41da-91b9-ebe2ecc83b66 | |
| relation.isOrgUnitOfPublication | 7c022d60-21d5-497c-b552-95e489a06569 | |
| thesis.degree.level | Doctoral |