On-Demand In Vivo Reprogramming of Endogenous Extracellular Vesicles for Targeted Biotherapeutic Delivery
Lead Research Organisation:
UNIVERSITY OF OXFORD
Abstract
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.
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.
People |
ORCID iD |
| Dhanu Gupta (Principal Investigator) |