Thesis

Investigating potency and efficacy of mRNA lipid nanoparticle systems and targeting lymph node

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Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17107
Person Identifier (Local)
  • 202066616
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • mRNA lipid nanoparticle (LNPs) based vaccines played a crucial role in dealing with the COVID19 pandemic. The primary function of LNPs is to encapsulate and deliver mRNA to the target site, facilitating its release into the cytosol, thereby eliciting an immune response against the antigen transcribed from the mRNA. Despite LNP's first approval in 2018 for delivering siRNA to the liver cells, LNPs face challenges such as endosomal escape, stability, and extrahepatic targeting. The components of LNPs need to be optimised with in vitro and in vivo studies to address these challenges. This thesis aimed to investigate the efficiency of mRNA-LNP systems. The study evaluated ionisable lipids such as ALC-0315, SM-102, and Polyethylene glycol (PEG) lipids, including DMG-PEG2k and ALC-0159. From the in vitro and in vivo studies, SM-102 LNPs were selected as a lead formulation and moved further with testing the ionic strength of the encapsulation buffer. This study showed that the concentration of citrate buffer also had a significant role in transfection efficiency; increasing the ionic strength from 50 mM to 300 mM negatively impacted the transfection efficiency. Additionally, the efficacy of a microfluidic-based rapid mixing method (MF) was evaluated using the Design of Experiment (DoE) approach to reveal the importance of process parameter and their interactions and quadratic effects. Subsequently, an in vivo study (using ovalbumin (OVA) mRNA in varying doses) highlighted the sex-specific immune response, irrespective of the protein expression. The final study focused on using biotinylated LNPs to target the lymph node, exploiting the strong interaction between avidin and biotin. Overall, this thesis provided insight into investigating mRNA-LNP systems, demonstrating potential strategies to enhance the efficacy of mRNA-based vaccines, which is crucial for advancing therapeutic applications.
Advisor / supervisor
  • Rattray, Zahra
  • Perrie, Yvonne
Resource Type
DOI
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file details PDF of thesis T17107 2024-10-02 公开 下载