Oral Presentation Australasian RNA Biology and Biotechnology Association 2024 Conference

Synthetic messenger RNA delivery in healthy liver, liver disease and cancer (112676)

Laura Leighton 1 , Yee Jing Gee 1 , Sachithrani U. Madugalle 1 , Maria Victorova 1 , Nissa L Carrodus 1 , Kim R Bridle 1 , Sidney A Howell 1 , Xiaowen Liang 1 , Gregory C Miller 1 , Darrell H. G Crawford 1 , Timothy R Mercer 1 , Seth W Cheetham 1
  1. The University of Queensland, St Lucia, QLD, AUS

Synthetic messenger RNA encapsulated in lipid nanoparticles (mRNA-LNP) is a transient gene delivery substrate which came to worldwide attention after its successful application for COVID-19 vaccines. Several publications have demonstrated that when delivered by the intravenous route, mRNA-LNPs accumulate in the liver and the encoded gene product is predominantly expressed by hepatocytes. However, relatively little is known about the effect of liver disease on mRNA-LNP uptake or expression, or the delivery of mRNA-LNPs to liver tumours. We set out to characterise the expression of mRNA-LNP-encoded reporter genes in mice with healthy and fibrotic livers, and in mouse models of primary and secondary liver cancer, using a variety of orthogonal biochemical and imaging techniques. We found that delivery of mRNA-LNPs is unaffected by mild chemical damage, but moderately impaired by severe fibrosis and cirrhosis. Delivery of mRNA-LNPs to liver tumours is comparable to the adjacent liver tissue in spontaneous hepatocellular carcinoma, xenografted hepatocellular carcinoma, and xenografts derived from lung and colorectal cancers. However, delivery of mRNA-LNPs to tumours located elsewhere in the body is weak to undetectable. Our results suggest that hepatic location, rather than cellular identity, is important for mRNA-LNP uptake into primary and secondary liver tumours. Our work demonstrates the range of possible outcomes after mRNA-LNP administration at both the whole-organ, whole-tumour and cellular scales, providing an important resource for investigators aiming to use mRNA-LNPs in hepatic biology research or as future treatments for liver disease and liver cancer.