Surface Engineering of Protein Nanoparticles for Intranasal Delivery
Author(s)
Pho, Thomas
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Abstract
Intranasal delivery of vaccines offers a promising alternative approach to invasive intramuscular
injection, with additional benefits such as inducing mucosal antibodies and cellular responses to
neutralize pathogens before entering systemic circulation. However, nasal secretions and mucosa
are biological barriers that have been shown to inhibit the delivery of antigens and nanoparticles
to nasal-associated lymphoid tissue (NALT) and lungs. Protein nanoparticles are composed of
proteins at high mass-to-carrier ratio, while allowing for biocompatibility and tunable
physiochemical properties. They have been demonstrated to be effective vaccines and drug
delivery carriers. The surfaces of these carriers can be decorated with coatings and chemical
modifications, which can alter transport and immune responses due to their interaction with
biological barriers and cells. In this work, we evaluate intranasal localization of engineered
surface-coated protein nanoparticles and assess their immune response following vaccination in
murine models. To understand the principles behind modifying nanoparticle surface formulations
will assist in improving accessibility to the NALT and delivery of protein-based nanocarriers for
non-vaccine intranasal delivery. We screened ovalbumin nanoparticles coated with polyethylene
glycol (PEG) and layer-by-layer coating of trimethyl chitosan and CpG oligodeoxynucleotide
adjuvants delivered intranasally in murine models and compared to unmodified protein
nanoparticles. The localization and biodistribution were observed using non-invasive in vivo
imaging and for regional localization and tissues using both flow cytometry and
immunohistochemistry. Surface-coated nanoparticles were used for intranasal vaccination in a
murine model and characterized for the mucosal antigen-specific response, as well as systemic
humoral and cellular responses through antibody titers and T-cell activation. The findings and
designs from screening coatings with model ovalbumin nanoparticles were incorporated into
influenza antigen nanoparticle formulations. Two influenza antigens (hemagglutinin and matrix
protein 2 - (A/California/07/2009(H1N1)) were used to construct a subunit protein nanoparticle
vaccine with surface structure control using bioconjugation. A layer-by-layer (LBL) coating
approach was used to survey specific formulation based on their administration route. Overall, our
findings indicated that LBL surface formulation improved nasal biodistribution and immune
response upon intranasal delivery, highlighting a new nanoparticle formulation for nasal vaccines.
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Date
2023-12-07
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Text
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Dissertation