Date Approved
5-19-2024
Embargo Period
5-19-2027
Document Type
Dissertation
Degree Name
Ph.D. Biomedical Engineering
Department
Biomedical Engineering
College
Henry M. Rowan College of Engineering
Advisor
Rachel Riley, Ph.D.
Committee Member 1
Mark Byrne, Ph.D.
Committee Member 2
Sophia Orbach, Ph.D.
Committee Member 3
Andrea Bottaro, Ph.D.
Committee Member 4
Kathryn Behling, M.D. Ph.D.
Keywords
Drug Delivery;Endometrial Cancer;Immunomodulation;Nucleic Acids;Pregnancy
Abstract
Nucleic acids are one of the most dynamic biomolecules capable of transiently controlling gene expression within cells to study and treat disease. Lipid nanoparticles (LNPs) are the most preclinically and clinically advanced nucleic acid delivery platforms with proven efficacy in delivering both siRNA and mRNA. This dissertation develops and applies LNPs specifically towards the treatment of reproductive diseases. First, we design an LNP formulation optimized for delivery to endometrial cancer cells using a systematic design process, establishing the first LNP platform developed for this application. Next, we develop LNPs for the delivery of IL-4 mRNA (IL-4-LNPs) and IL- 13 mRNA (IL-13-LNPs) to trophoblasts with the intent to control macrophage phenotype in the placenta. Finally, we develop two targeting strategies to increase placenta-specific delivery of LNP payloads. First, we surface-conjugated anti-plCSA antibody fragments (Fabs) to the surface of LNPs to promote cell-specific binding. Second, we developed a novel mRNA construct encoding a self-targeting IL-4 (HT-4) mRNA sequence delivered via LNPs, which overcomes challenges associated with ligand targeting. Our second and third objectives demonstrate that LNPs can target the placenta and release immunologically active payloads, towards the goal of local immunomodulation. Together, this dissertation presents new technologies and opportunities to use LNPs to treat reproductive diseases to improve outcomes for patients.
Recommended Citation
Hofbauer, Samuel, "LIPID NANOPARTICLES FOR GENE THERAPY AND IMMUNOMODULATION IN REPRODUCTIVE HEALTH" (2024). Theses and Dissertations. 3354.
https://rdw.rowan.edu/etd/3354
