Description

The Problem

A critical unsolved problem in drug delivery is escaping the ‘endosomal barrier’. When a cell engulfs a drug it encloses it within a membrane sphere called the endosome. This locks the drug away in an intracellular compartment where its effect is limited. Various strategies have been attempted to bypass this barrier, such as adding positively-charged lipids or cell-penetrating peptides. However, no endosomal escape strategies have yet achieved success in demonstrating efficacious delivery, repurposability across drug classes, and low cost. We aim to repurpose a novel needle-like protein that can mechanically rupture this endosome in response to the endosome’s chemical environment. Our simple, mechanical approach is innovative and we seek to prove that our innovative mechanical approach it fulfils all the criteria for an effective, modular delivery system via proof-of-concept experiments in tumour models.

Our Solution

Refractile bodies (R bodies) were discovered in the 1970s as natural toxin-delivery systems. R bodies are sharp, coiled protein ribbons that can rapidly extend and rupture endosomes when engulfed by cells. Recent research has highlighted that instead of delivering toxins, they could be repurposed for delivering drugs (Polka & Silver 2016). R bodies could act as a ‘Trojan horse’ by hiding pharmaceuticals on their inside and carrying molecules that target R bodies to particular cells (e.g. cancer cells) on the outside. Once engulfed into endosomes in human cells, the R bodies can break them and release their payload into the cell cytosol. Different drugs and targeting molecules on the R body could be exchanged while keeping the same R body scaffold, thereby creating a modular delivery system that can improve treatment outcomes for a wide range of diseases. This could, for example, improve the potency of chemotherapeutics (Polli et al., 2022), or the efficacy of fragile anti-sense oligonucleotides (Li et al., 2023).

Our Inspiration

Naturally found in the microbe Pseudomonas aeruginosa, R body proteins provide evolutionary advantages. Our team was inspired by these so-called ‘killer’ paramecia, which contain bacteria that can enter other paramecia, and, with R-bodies, rupture and release toxins into rival paramecia. We saw this unique toxin delivery system and considered how it can be utilised to enhance drug efficacy in humans.