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Vasudevan, Akshaya (2024) Part A: RNA Therapeutics. Development and challenges in nanoparticle delivery/ Part B: Synthesis and characterisation of supramolecular polyplexes for mRNA delivery. MRes thesis, University of Nottingham.

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Abstract

Part A:

With the approval of mRNA vaccines for the COVID-19 pandemic, RNA therapeutics have gained significant attention. They can be used for treatment, prophylaxis, or amelioration of diseases such as cancer, infectious diseases, as well as rare genetic disorders. With a suite of RNAs and delivery systems at our disposal a tailored approach can be designed for any target condition. Despite this, there are few clinically approved RNA treatments. In practice, RNA therapeutics face several challenges primarily enzymatic degradation, immunogenicity, low cellular uptake, and less endosomal release each of which must be mitigated before clinical approval is achieved. This review introduces the types of RNA, their delivery systems, and the challenges faced in RNA therapeutics. It also briefly discusses current advancements in designing RNA nanoparticles.

Part B:

mRNA has shown tremendous potential for treatment and amelioration of a multitude of disease conditions including cancer. It has been engineered to deliver antigens to increase the immune response to cancer cells or express cancer cell proliferation suppressants. However, the growth of mRNA therapeutics is limited by the poor transfection of naked mRNA in the cell owing to its degradation by extracellular as well as intracellular components. Cationic polymers have emerged as promising delivery vectors demonstrating successful encapsulation and facilitating cellular uptake.

This project aimed to synthesise a cationic monomer of triethylenetetramine with oligopeptide terminals (TETA-2L2) for use as a delivery vector. It also aimed to modify this cationic monomer with side chains of varying hydrophobicity and hydrophilicity. Further, the aim was to design polyplex formulations with cationic monomers for mRNA delivery with low toxicity and high transfection in triple-negative breast cancer cells. It was observed that polyplexes with a 25:75 ratio of TETA-2L2 and TETA-2L2-2C4 and an N/P ratio of 32 demonstrated high uptake efficiency, efficient mRNA transfection, and low cytotoxicity (>96% viability). These results support their study for further investigation including determining endosomal escape, pathway for internalisation, and comparison with other nucleic acids such as scrambled siRNA or siRNA. The study's findings could help optimise mRNA delivery methods and overcome the obstacles associated with mRNA-based therapeutics.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Alexander, Cameron Harding, Stephen
Keywords:	mRNA delivery systems; Challenges and advances
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools:	UK Campuses > Faculty of Science > School of Biosciences
Item ID:	79504
Depositing User:	HARDING, Prof Stephen
Date Deposited:	13 Dec 2024 04:40
Last Modified:	13 Dec 2024 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/79504

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