ABCs of LNPs - Advanced Biophysical Characterisation of lipid nanoparticles for mRNA therapeutics

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Advanced Biophysical Characterisation (ABCs) of LNPs is a collaborative project between Nanovation UK, STFC and NML to characterise lipid nanomedicines to create a cost-effective and accessible treatment for liver disease.?Currently, the only curative treatment for liver disease is transplantation. Reducing the number of patients progressing to end-stage liver cirrhosis and liver cancer will have a significant impact for patients.The use of lipid nanoparticles (LNPs) as delivery vehicle of the mRNA vaccines against Covid-19, has emphatically shown these systems a) are safe and effective in humans, b) can be developed at unprecedented speed, c) can be manufactured at scale and d) can be produced at low cost (approx. £15 a dose). LNP-mRNA based therapies have been proven to reverse liver fibrosis but, due to inefficient LNP-mRNA delivery to the liver, required repeated, high dosing which resulting in significant and adverse toxicity. Therefore improved LNP delivery systems are required.A major outstanding challenge in advancing LNP technologies is a lack of understanding of how LNP structure impacts their performance as nanomedicines. This means most discovery programs rely on primarily empirical screening of large libraries of LNPs. At Nanovation, we have a library of novel lipids and LNP compositions and a basic design, make and test cycle for LNP optimisation. Subsets of our LNPs fulfil our assessment quality criteria but do not perform as expected. We suspect this is due to the influence of particle structure but have a limited ability to quantify this. Generating scientific understanding of the structural similarities / differences between the structure of our highest performing LNPs and low performing LNPs is key to developing ways to maximise the performance of our LNP products. This project will address these challenges.