Theses and Dissertations

ORCID

0000-0001-9386-7778

Advisor

Fitzkee, Nicholas

Committee Member

Emerson, Joseph

Committee Member

Johnson, Christopher

Committee Member

Creutz, Sidney

Committee Member

Werfel, Thomas

Date of Degree

8-12-2026

Original embargo terms

Visible MSU Only 1 year

Document Type

Dissertation - Campus Access Only

Major

Chemistry

Degree Name

Doctor of Philosophy (Ph.D.)

College

College of Arts and Sciences

Department

Department of Chemistry

Abstract

When nanoparticles enter biological fluids, they are rapidly coated by proteins to form a protein corona that defines their biological identity and governs interactions with cells and the immune system. Despite growing recognition of the corona's importance, a molecular-level understanding of how specific proteins adsorb onto nanoparticle surfaces and how the physical character of that adsorption shapes downstream biological outcomes remains limited. This dissertation addresses both dimensions of this challenge, establishing a framework for predicting and engineering protein corona behavior. In the first project, competitive binding dynamics among four key serum proteins, bovine serum albumin, transferrin, fibronectin, and immunoglobulin G, on gold nanoparticles were characterized using ¹³C-methyl NMR spectroscopy. A hierarchical binding model was established to enable rational control of the composition of the multi-protein corona. Pre-coating nanoparticles with an engineered four-protein corona produced formulations that selectively enhanced cancer cell uptake while reducing macrophage recognition in vitro. In tumor-bearing mice, the optimized formulation achieved approximately 4% injected dose per gram of tumor tissue, a 6.5-fold improvement over bare nanoparticles, demonstrating that deliberately engineered coronas can overcome the fundamental delivery limitations that have long hindered the clinical translation of nanomedicines. The second project interrogates why the same protein can produce dramatically different immune outcomes depending on how it adsorbs. Using complement component C3d as a model complement fragment, the first backbone resonance assignment of this 33 kDa protein was completed by solution NMR spectroscopy, confirming a rigid, α-helical solution structure. Biophysical characterization across polystyrene, PLGA, liposome and gold nanoparticle platforms revealed that C3d forms coronas of comparable thickness through fundamentally distinct thermodynamic mechanisms, with NMR linewidth analysis distinguishing hard corona immobilization on polystyrene from soft corona dynamics on the other surfaces. Orientation-controlled conjugation of single-cysteine C3d variants to gold nanoparticles demonstrated that macrophage internalization varies by over 100-fold depending solely on which face of the protein is presented to the nanoparticle surface. Taken together, these findings reveal that protein orientation at the nanoparticle interface is as consequential as protein identity in determining biological outcomes, providing a molecular foundation for designing next-generation nanomedicines with predictable, programmable immune and targeting behavior.

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