Date Approved
5-27-2025
Embargo Period
5-27-2027
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
Erik Brewer, Ph.D.
Committee Member 3
Andrea Vernengo, Ph.D.
Committee Member 4
James Holaska, Ph.D.
Keywords
Drug Delivery;Lipid Nanoparticles;Nucleic Acids;Placenta;Preeclampsia
Abstract
The goal of this dissertation was to design and develop novel lipid nanoparticle (LNP) drug delivery platforms for nucleic acid delivery to the placenta to treat placental dysfunction. Nucleic acids transiently modulate gene expression and have high potential as a therapeutic modality for placental dysfunction-related disorders, such as preeclampsia, which collectively affect 10-15% of pregnancies. First, we employ Design of Experiment approaches to investigate LNP design parameters for LNP-mediated mRNA delivery to placental cells. We utilize an optimized LNP formulation to deliver placental growth factor mRNA, an angiogenic factor downregulated in preeclampsia. Next, we characterize the hypoxic microenvironment of the dysfunctional placenta using 1st and 3rd trimester in vitro models. We investigate how hypoxia impacts LNP delivery to provide insights for LNP design for gene therapy in the hypoxic, diseased placenta. Next, we characterize an in vivo model of placental dysfunction and hypoxia utilizing endothelial nitric oxide synthase knockout (eNOS⁻/⁻) mice. Finally, we exploit the hypoxic microenvironment of the dysfunctional placenta to design a hypoxia-responsive ionizable lipid which, when complexed into LNPs, promotes delivery to hypoxic placental cells. Together, this dissertation provides insights into placental dysfunction that inform the design of novel LNP technologies to treat placental dysfunction-related disorders and improve patient outcomes in maternal-fetal health.
Recommended Citation
Young, Rachel, "DESIGN AND DEVELOPMENT OF LIPID NANOPARTICLES FOR PLACENTAL GENE THERAPY" (2025). Theses and Dissertations. 3361.
https://rdw.rowan.edu/etd/3361
