Excellence in Research - Modified MSC-Derived Exosomes for Reprogramming Macrophage

Large bone injuries can happen because of accidents, infections, weak bones, or surgeries to remove tumors. These problems affect many people and are hard for doctors to treat. One major reason bones heal slowly is because of long-lasting inflammation.

There is an important immune cell called a macrophage that plays a big role in inflammation. Macrophages can be in one of two forms: M1 or M2. M1 causes inflammation, while M2 reduces it.

Changing M1 to M2 can help heal bone injuries. Stem cells from bone marrow, known as mesenchymal stem cells (MSCs), can release tiny particles called exosomes, which help control the immune system. However, using exosomes still has some challenges.

This project aims to create a new type of exosome called modTEx. modTEx is designed to target macrophages and change them from M1 to M2, reducing inflammation and helping bones heal. This project will have a wide impact on medicine, engineering, nanotechnology, and drug delivery. It will also focus on mentoring and training the next generation of STEM students.

It will offer biomedical research opportunities to underrepresented students from historically black colleges and universities (HBCUs). In addition, outreach activities like workshops or seminars will give students hands-on training and mentorship experiences. By creating a diverse and inclusive research environment, this project aims to inspire and empower future minority scientists.

This project aims to engineer MSC-derived exosomes (MSC-Exo) for precise immunomodulatory regulation and enhanced bone repair. These engineered exosomes target and reprogram macrophages to optimize immune responses and bone healing. By integrating stem cell biology, metabolic engineering, nanotechnology, advanced imaging, and animal injury models, the research seeks to advance our understanding of immunomodulation and bone repair, with broad implications for medicine, bioengineering, and pharmacology.

Addressing large bone defects, particularly those complicated by infections and immune diseases, the study focuses on balancing the roles of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Prior research indicates that MSC-Exo can be enhanced through metabolic engineering to increase their therapeutic potential and specificity.

Preliminary findings suggest that exosomes from cytokine-treated MSCs (TEx) exhibit increased osteogenesis and anti-inflammatory properties. The project will test the hypothesis that TEx, designed for precise macrophage targeting, can effectively reprogram macrophages and promote bone healing. This will be achieved through three specific aims: 1) Generating TEx for macrophage reprogramming; 2) Modifying TEx for precise targeting; and 3) Evaluating their effects in a rodent bone defect model.

The research promises to establish a foundation for a cell-free, exosome-based approach to bone repair. Additionally, it will impact the broader scientific community by offering potential solutions for immune-related inflammatory diseases and providing multidisciplinary research opportunities for underrepresented undergraduate and graduate students at the University of Maryland Eastern Shore, fostering the next generation of minority STEM scientists.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.