Abstract

mRNA-based therapeutics open a new era for the prevention and treatment of a wide range of diseases. However, existing mRNA delivery vehicles have limited repertoires for dendritic cell targeting and intranasal administration which are two paramount delivery pathways of significant advantages for treating cancer and infectious respiratory diseases. Adenovirus (Ad) with well-deciphered viral genomes and intensive-studied structure biology has been developed for DCs-targeted cancer vaccines and intranasal COVID vaccines. In light of these virtues, Ad presents as the “off-the-shelf” tool possessing well-defined manufacturable capabilities and translatable feasibility that perfectly complements the current limitations of mRNA delivery. In this study, we developed a novel “Ad piggyback protamine (AdPro)” mRNA delivery platform built upon the utilization of Catcher/Tag molecular glue to accomplish specific anchoring protamine to hexon locales of Ad capsid at a molecular precision level. Our pilot study manifested that “AdPro” was a potent mRNA delivery vehicle and integration of Catcher/Tag technology enabled us to manipulate the construction process with great precision, offering the opportunity to engineer other capsid proteins to equip Ad with both mRNA delivery and cell targeting ability. Further investigation may consider evaluating other mRNA constructs, such as circRNA, or other advanced mRNA binders, such as RALA to optimize the delivery efficiency as well as genetically engineering Ads fiber protein with cell targeting ligands while retaining the SpyTag-incorporated hexon as the mRNA binders anchoring site to develop the multi-functional delivery platform.

Committee Chair

David T Curiel

Committee Members

Gregory M. Lanza Michael Vahey

Degree

Master of Science (MS)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Thesis

Date of Award

Spring 5-15-2023

Language

English (en)

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