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MSE PhD Prospectus Defense: Matthew Taylor

TITLE: Active Targeting of the Lipid Nanoparticle Protein Corona for Directed Delivery of Gene Therapeutics to Specific Tissues

ADVISOR: Mark Grinstaff, Chem, MSE, BME, MED

COMMITTEE: Michael Albro, ME, MSE, BME; Brianne Connizzo BME, ME; Timothy O’Shea BME, MSE

ABSTRACT: Although the potential of nucleic acid-based gene therapy to directly modulate the foundational causes of disease has been recognized for decades, its ultimate implementation has been historically impeded by successful delivery of functional DNA or RNA. Gene therapeutics must overcome a hierarchy of obstacles to impart a physiological effect and the development of LNP systems has produced a delivery strategy that shields the gene therapeutics from enzymatic degradation, facilitates endocytosis across the cell membrane, and avoids the drawbacks of viral delivery vectors such as immunogenicity and packing capacity. Recently, the focus of LNP development has evolved to target delivery to specific tissues/organs to increase dose efficacy and decrease off-target effects. Historically, targeted delivery has centered on the decoration of the LNP exterior surface with ligands such as peptides, antibodies, or other moieties specific to the target tissue and has been termed as “active targeting.” Modification of the LNP with targeting ligands or specific surface properties to drive active targeting, however, assumes the native LNP directly interacts with the cell surface. This, however, is not the case as LNPs are rapidly coated in a layer of adsorbed biomolecules upon administration and this corona of adsorbed proteins thus establishes a new exterior surface to the LNP that will determine subsequent cellular interactions and may block presentation of active targeting moieties. Instead of decorating active targeting moieties onto the LNP surface that will later be blocked by the adsorbed protein corona, targeting moieties can be conjugated to the protein corona itself and adsorbed onto the LNP prior to in-vivo administration—thereby pre-coating the LNPs in an actively-targeting protein corona. Here, this method of utilizing an actively targeted LNP protein corona will be analyzed for targeting gene therapeutics to HER2+ tumors of both in-vitro and in-vivo.