Thesis

Developing the next generation of mRNA vaccines : redefining mRNA delivery through rational LNP manufacturing, formulation and targeting studies

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Awarding institution
  • University of Strathclyde
Date of award
  • 2026
Thesis identifier
  • T18053
Person Identifier (Local)
  • 202255814
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Department, School or Faculty
Abstract
  • Lipid nanoparticles are now the most clinically advanced lipid-based nucleic acid delivery system – offering a precise and efficient method to intracellular nucleic acid delivery. However, since their clinical success during the COVID-19 pandemic, LNPs have lacked in areas such as fast and simple formulation screening, enhanced endosomal escape and extra-hepatic targeting capabilities. Enhanced screening techniques and optimised manufacturing could help alleviate these issues. This thesis focused on increasing the availability and accessibility of LNP formulation and manufacture. Initial studies looked at a comparison of formulation screening methods: OFAT, manual, and automated DoE and identified that conclusions drawn from each method were not identical, highlighting how manufacturing can affect the CQAs and hence functionality of LNPs. Following studies then investigated low-cost microfluidic mixers, including pipette mixing as a formulation and high-throughput screening tool, demonstrating the feasibility and efficacy during manufacture. This thesis also identified the need for orthogonal and additional methods to screen RNA encapsulation efficacy in lipid nanoparticles as well as mRNA functionality, investigating HPLC-PDA quantification and ex vivo cellular systems as functional assays. Lastly, final studies were focused on extra-hepatic targeting of lipid nanoparticles, aiming to successfully deliver mRNA to M2-subtype macrophages through post-insertion of a targeting ligand on the outside layer, demonstrating enhanced protein expression for select formulations. In conclusion, this thesis provided insight into how mRNA vaccine development can be aided by refining current formulation, manufacturing and targeting procedures.
Advisor / supervisor
  • Perrie, Yvonne
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