| Project Detail |
Examining lipid nanoparticle use for breast cancer treatment
The ERC-funded MaxFUSE LNPS project will study how nanomedicines can be engineered to improve the treatment of advanced breast cancer. The project will examine the mechanisms underlying how lipid nanoparticles (LNPs) deliver mRNA payloads into cells. The use of LNPs in cancer treatment presents challenges, and current LNP formulations face issues with toxicity, performance and specificity. One of the key steps in the LNP delivery process, endosomal escape, is particularly inefficient. Researchers will further investigate endosomal escape and aim to enhance it through nanoscale engineering. Project objectives include developing models of breast cancer endosomes, designing LNPs for enhanced endosomal fusion and validating engineered LNPs for increased fusion and lower toxicity in breast cancer treatments.
There is a strong need for personalised genetic medicines for the treatment of advanced breast cancer. LNP-mRNA nanomedicines have already been proven as safe and cost effective in the SARS-CoV-2 vaccines. However, cancer treatments often require (i) repeat dosing (ii) controlled immune response (iii) adaptability to combat drug resistance. There are several LNP-RNA clinical cancer trials ongoing, many of which have reported challenges with toxicity, performance and specificity (off target effects). For an LNP-RNA cancer therapeutic to function, they need to localise in the correct organ, enter the cancer cells and escape the cellular (endosomal) processing pathway to release their RNA cargo. In current LNP-RNA formulations only a small fraction (<10 %) of LNPs successfully escape the endosome. However, these ‘null’ LNPs can still contribute to toxicity which places huge restrictions on their clinical application and performance. The aim of this proposal is to provide mechanistic insight into the endosomal escape of LNPs and use nanoscale engineering to target the endosome and improve LNP endosomal escape. This is particularly relevant in breast cancer as the majority of LNP systems are optimised for liver applications and designed to undergo fusion under ‘healthy’ endosomal conditions. In breast cancer, the composition (lipid, protein) and environment (pH) of the endosome differ significantly between healthy and cancer cells.
Objectives:
- Use omics approaches to quantify key differences in the endosome in healthy and breast cancer sub type cells and develop breast cancer sub type endosome models
- Design LNPs with enhanced fusion to endosomes using (i) lipid composition (ii) protein – protein / lipid interactions (iii) pH mediated fusion
- Validate novel LNPs with increased endosomal fusion and lower toxicity for breast cancer treatment |
