Cells in the body will be reprogrammed to produce their own therapeutic delivery vehicles on demand, triggered only when inflammation strikes. This matters because extracellular vesicles (EVs)—tiny particles that cells naturally release to carry biological cargo—are promising for treating inflammatory diseases like multiple sclerosis, sepsis, and Crohn’s disease, but two obstacles block their clinical use: they are difficult to produce at scale, and they do not survive long enough in the body to work effectively. Current methods rely on complex bioreactor systems to manufacture EVs outside the body, which is costly and inefficient. This project sidesteps those problems by using clinically approved gene-delivery tools—adeno-associated viruses and lipid nanoparticles carrying mRNA—to instruct the body’s own cells to generate EVs that display decoy receptors on their surface. These decoys neutralise harmful inflammatory signals only when and where inflammation occurs. The approach combines the targeted delivery of viral vectors with the broad tissue reach and low immune response of EVs, eliminating the need for external manufacturing. If successful, this platform could produce safer, longer-lasting treatments that require less frequent dosing and reduce side effects. It could also be adapted for cancer therapy and regenerative medicine, offering a scalable, off-the-shelf solution for multiple diseases.
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Extracellular vesicles (EVs) are small particles naturally released by cells that carry important biological molecules, making them promising tools for delivering therapies to treat diseases such as inflammation, cancer, and autoimmune disorders. However, two major challenges hinder their clinical application: producing EVs at a large scale and ensuring they persist in the body long enough to be therapeutically effective. This project aims to overcome these challenges by developing innovative technology to engineer the body’s own cells to produce therapeutic EVs. Using clinically approved gene delivery systems like adeno-associated viruses (AAVs) and lipid nanoparticle (LNP)-encapsulated mRNA, we will reprogram cells in the body to generate EVs that display specialized receptors on their surface exclusively during inflammation. These engineered EVs will act as “decoys” to neutralize harmful inflammatory signals in diseases such as multiple sclerosis, sepsis, and Crohn’s disease. While AAV vectors are highly effective for targeting the liver due to their natural tissue tropism and ability to deliver genes safely only at low doses, EVs offer a safer and more versatile alternative for delivering therapies across complex biological barriers and into tissues that AAVs cannot efficiently access without inducing toxicity. By combining the targeted delivery efficiency of AAVs with the broad tissue distribution and low immunogenicity of EVs, this strategy eliminates the need for complex bioreactor systems, enabling the development of a scalable, off-the-shelf therapeutic product. The research will focus on three main objectives, each addressing a critical challenge: 1. Optimizing EV Engineering: We will use synthetic biology tools to develop small peptide tags that improve the display of therapeutic molecules on EV surfaces. This approach addresses the challenge of inefficient and inconsistent EV modification, enabling the scalable production of functional, disease-targeting EVs. 2. Developing Inflammation-Responsive Genetic Circuits: To solve the problem of uncontrolled EV production, we will design precise genetic circuits that trigger the secretion of engineered EVs only during inflammation. This ensures safe and targeted delivery, providing treatment exactly when and where it is needed. 3. Preclinical Testing in Disease Models: To validate the therapeutic potential, we will test these engineered EVs in preclinical models that mimic key inflammatory diseases, including multiple sclerosis, sepsis, and Crohn’s disease. Additionally, we will utilize 3D human organoid systems to evaluate the safety and effectiveness of the treatment in human-relevant environments. If successful, this project will lead to safer, more effective treatments for inflammatory diseases, reducing the need for frequent drug dosing and minimizing side effects. This versatile platform could also be adapted for other conditions, including cancer therapy and regenerative medicine, making it a transformative solution for a range of health challenges. By directly addressing the current limitations of EV-based therapies, this project aligns with the BBSRC’s long-term priorities in advancing bioscience technologies and improving health through innovative research. It offers scalable, sustainable solutions to complex medical problems and holds significant potential to transform patient care and drive the future of precision medicine.
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