A Novel mRNA Delivery Strategy Employing Adenovirus Piggyback mRNA Binders via Catcher/Tag Molecular Glue
Date of Award
Master of Science (MS)
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.
David T Curiel
Gregory M. Lanza Michael Vahey
Available for download on Sunday, December 24, 2023