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Author ORCID Identifier


Campus-Only Access for Five (5) Years

Document Type


Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded


Month Degree Awarded


First Advisor

Vincent M. Rotello

Second Advisor

D. Joseph Jerry

Third Advisor

Michelle E. Farkas

Fourth Advisor

Ashish Kulkarni

Subject Categories

Biochemical and Biomolecular Engineering | Biomaterials | Biotechnology | Molecular, Cellular, and Tissue Engineering | Polymer Science


The development of pharmaceutical technology has enabled the treatment of diseases that were once considered ‘undruggable.’ The advent of nucleic acid therapeutics has opened up new possibilities for targeting previously inaccessible pharmaceutical targets. Small interfering RNA (siRNA) has shown great potential in various biological applications, including disease treatment and tissue regeneration. Its ability to silence genes in a sequence-specific manner and target a wide range of proteins makes siRNA particularly attractive for medical applications. However, siRNA’s utility at the cellular level is limited since it cannot cross the plasma membrane by itself. Additionally, the lack of safe and effective delivery vectors remains a major challenge in this field. Nanocarrier technologies can encapsulate siRNA therapeutics and facilitate cell uptake, but they are often trapped and degraded in endosomes. An alternative approach is direct cytosolic delivery through a membrane-fusion-like mechanism, which enables the direct transport of cargo to the cytosol with highly increased therapeutic efficacies. In this thesis, my research focused on using poly(oxanorborneneimide) (PONI)-based polymeric nanoparticles to efficiently deliver siRNA therapeutics into the cytosol. The semi-arthritic characteristics of the PONI backbone facilitate efficient cytosolic siRNA delivery through a membrane-fusion-like mechanism. My work demonstrated the incredible versatility of PONI-based polymeric nanoparticles for siRNA therapeutics by varying their structural design with guanidinium, zwitterion, or quaternary ammonium groups and investigating their effects on anti-inflammation, anti-cancer, or anti-microbial therapies. In summary, this thesis presents a highly versatile and modular delivery platform for the efficient cytosolic delivery of siRNA in vitro and in vivo for a wide range of therapeutic applications. This represents a powerful direction for translational research in the treatment of pulmonary inflammation, triple-negative breast cancer, and biofilm-related wound healing.


Available for download on Sunday, September 01, 2024