Engineering lipid nanoparticles to target and escape the endosome, deliver their cargo and perform better as breast cancer therapies

Introduction

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:

1. Repeat dosing
2. Controlled immune response
3. Adaptability to combat drug resistance

Challenges in Current Treatments

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
• 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.

Proposal Aim

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 subtype cells and develop breast cancer subtype endosome models.
• Design LNPs with enhanced fusion to endosomes using:
  1. Lipid composition
  2. Protein–protein / lipid interactions
  3. pH mediated fusion
• Validate novel LNPs with increased endosomal fusion and lower toxicity for breast cancer treatment.