Author ORCID Identifier

0009-0004-8014-3366

Date of Award

8-2026

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Physical/Analytical Chemistry

First Advisor

Jason Evans

Second Advisor

Daniel Dowling

Third Advisor

Michelle Foster, Shailja Pathania

Abstract

Mass spectrometry has become an indispensable analytical platform for investigating complex biological systems owing to its sensitivity, selectivity, and molecular specificity. This Dissertation demonstrates the versatility of liquid chromatography-tandem mass spectrometry (LC-MS/MS) through three studies focused on nanoparticle characterization, protein structural analysis, and plasma proteomics. In Chapter 2, LC-MS methods were developed to characterize novel lipidoid incorporated into lipid nanoparticles (LNPs) and to evaluate their in vivo biodistribution following systematic administration. Comparative proteomic analysis of the resulting protein coronas revealed distinct differences between liver and lung targeting LNP formulations, providing insight into the potential role of adsorbed blood proteins in directing organ-specific delivery. In Chapter 3, an LC-MS/MS workflow was established to identify and confirm the native disulfide bond architecture of human insulin through the analysis of intact protein and Glu-C digested peptide and disulfide-linked peptide complexes. High-resolution precursor mass measurements together with tandem mass spectrometry sequencing ions enabled confident confirmation of native disulfide connectivity and demonstrated the utility of this analytical framework for proteins structural characterization. In Chapter 4, the challenges associated with the large dynamic range of the plasma proteome were addressed through the investigation of the incorporation of Adaptive Focused Acoustics (AFA) instrumentation developed by Covaris Inc. into immunoaffinity depletion workflows. AFA-assisted depletion improved the removal of highly abundant plasma proteins, expanded proteome coverage, and enhanced the detection of lower-abundance proteins associated with clinically relevant biological pathways while providing a workflow compatible with automation and high-throughput analysis. Collectively, these studies illustrate how advances in mass spectrometry can be integrated to address diverse analytical challenges in biomedical research. The methodologies developed throughout this Dissertation contribute to improved strategies for targeted nanoparticle delivery, protein structural characterization, and plasma biomarker discovery, highlighting the expanding role of mass spectrometry in translational research and precision medicine.

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