BLRD Merit Review Research Career Scientist Award

My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes. These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatment

for a diverse but specific group of medical conditions, i.e., inflammation related diseases including widespread brain inflammation related diseases, obesity, rheumatoid arthritis, nonalcoholic fatty liver disease (NASH), and cancer. The accumulation of inflammatory cells that release proinflammatory cytokines and chemokines not only

promote brain disease progression such as Gulf War Syndrome but also rheumatoid arthritis, obesity and/or cancer. These diseases pose special burdens on veterans who depend on the VA for healthcare. Since receiving my initial Research Career Scientist award, my research group has published more than 60

manuscripts on this subject. Collectively, our findings support continued funding of my team to investigate the following aims: (1). Develop a therapeutic strategy to target delivery of therapeutic agents to microglia for treatment of brain inflammation related diseases such as Gulf War Syndrome. Microglia cells respond vigorously

to both chronic disease and acute insults affecting brain function. Targeted delivery of therapeutic agents to microglia is needed but highly challenging. The results published from my group (Theranostics, 2022,1220-1246, Cell Host Microbe, 2022, 944-960, and Small 2022, 2105385) provide emerging evidence for the development

of edible exosome-like nanoparticles as a safe delivery system for targeting different tissues including brain microglial cells, either by systemic or oral administration. (2). Investigate the role of tumor exosomes in immunosuppression through induction of myeloid-derived suppressor cells, inhibition of dendritic cell

differentiation, and inhibition of activation of NK cell immunotherapy. This approach is supported based on our published results (Nature Communications. 2017 Feb 17;8:14448, Nature communications. 2015;6:6956). (3). Exosomes are released from non-tumor cells and we will determine their role in: (a) exosome accumulation in

adipose tissue (Diabetes. 2009 Nov;58(11):2498-505, Hepatology, 2013 57(3):1250-61), we will investigate the role of adipose tissue exosome-like vesicles in activation of macrophage-induced insulin resistance and induction of liver NKT cell anergy; and (b) investigate exosomes released from rheumatoid synovial fibroblasts and inhibit

regulatory T cell development. Their role in contributing to damaging joint cartilage will be further investigated. (4). Based on the results we published as listed below, we will further develop customized exosome-like nanoparticles from edible plants as therapeutic vehicles to treat/prevent specific disease. (a) Ginger exosome-

like nanoparticles (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG) to prevent DSS induced mouse colitis (Cell Host Microbe, 2018, p637-652). Oral administration of oat nanoparticles inhibits brain

inflammation and improves brain memory function of mice fed alcohol by targeting microglial cells (Small 2022, 2105385). We have shown that targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) are delivered to intestinal macrophages, brain microglia cells (Molecular therapy: 2015, Volume 24, Issue 1, p96–

105), inflammatory tumor sites (Cancer Research, 2015;75:2520-9) by edible and health plant derived ELN. Broccoli-derived nanoparticle inhibits mouse colitis by induction of tolerogenic gut associated dendritic cells (Molecular Therapy. 2017), and grape exosome-like nanoparticles induce intestinal stem cells (Molecular

Therapy. 2013 Jul;21(7):1345-57). Collectively, our findings will not only open up a new avenue for investigating ELNs as a means to protect against the development of inflammation related diseases such as alcohol induced liver and gut damage, brain and joint inflammation related diseases, but sheds light on studying the cellular and

molecular mechanisms underlying inter-species communication via edible plant-derived nanoparticles.