SmallTalks: How can neutrons help us develop better drug delivery systems?

Abstract 

Since the COVID-19 pandemic, mRNA vaccines have become widely known as a powerful drug-delivery system. These vaccines use tiny lipid nanoparticles (LNPs) to deliver genetic instructions inside our cells. While the particles are taken up efficiently, a major challenge remains: once inside the cell, they become trapped in endosomes, which are membrane-bound compartments that typically recycle cellular material.

Most LNPs are degraded inside endosomes, and only a small fraction of the delivered mRNA successfully escapes and is released into the cell cytosol. This process, known as endosomal escape, is essential for delivered mRNA to have the desired therapeutic effect, and is one of the biggest bottlenecks in RNA therapeutics development. A better understanding of endosomal escape mechanisms could lead to improved and new treatments for various diseases.

To address this problem, we create simplified model membranes in the lab that mimic the membranes of the endosomes. We then use neutron reflectometry, a technique that can reveal the structure of thin films and biological membranes at the nanometer scale, to study how LNPs interact and affect these membranes. By uncovering the biophysical mechanisms of endosomal escape, our work aims to support the design of more effective RNA delivery systems.