A Comprehensive Supramolecular Approach for an RNA vaccine for Influenza A (H1N1)

*The development of vaccines is key for disease prevention, and is a major focus globally in the healthcare sector. Seasonal influenza is an acute respiratory infection caused by influenza viruses which circulate in all parts of the world. Seasonally, it remains a persistent health threat and has been declared an epidemic in some states. Typical vaccines have been less effective against rapidly evolving pathogens such as influenza. A new class of vaccines based on nucleic acids, namely RNA, have recently been developed and show immense promise due to their robust nature, short manufacturing times and enhanced efficacy. Here we propose an RNA delivery system based on a supramolecular assembly approach for the vaccination of influenza A H1N1 strain. Specifically, a π-amphiphile will be used as the platform molecule for covalent RNA conjugation and delivery. A messenger RNA (mRNA) targeting the hemagglutinin (HA) gene from a model influenza virus strain will be employed as the therapeutic (H1N1/PR8-HA). The central π-amphiphile moiety will be functionalized with the mRNA strand via a redox responsive disulfide bond, and hydrophilic oligo-oxy aryl groups connected via a hydrogen bonding unit to promote self-assembly. Steric stabilization will be afforded to the surface decorated mRNA to protect from enzymatic hydrolysis in the complex biological environments, through co-assembly with an analogue π-amphiphile which has been alternatively decorated with poly(ethylene glycol) (PEG) chains. Efficient intracellular transport of the delivery vehicle to achieve optimum mRNA transfection will be achieved through the incorporation of a TAT-peptide on the PEG chain end. The therapeutic efficacy of the nanoassembly will be evaluated through transfection efficacy in macrophage cell lines. Overall, this proposal aims to lay the groundwork for extending the scope of RNA vaccines by exploring the potential of supramolecular assemblies as a delivery vector.