At the Ibrahim Laboratory, we are interested in understanding how EVs signal to tissue, especially in a therapeutic context. We're also interested in their contents—namely small non-coding RNAs, which alter the behavior of target cells by regulating certain genes. By understanding EVs and their bioactive contents, we gain a better understanding of the mechanisms involved in tissue healing and repair and can use that knowledge to engineer effective next-generation therapeutics against inflammatory and fibrotic diseases, including those of the heart. Major discoveries have included identifying and describing the mechanism of several EV contents, including micro RNAs (e.g., miR-146a, miR-210, miR-181b, miR-26a and miR-92a) as well as Y-derived small RNA (EV-YF1). A major discovery included the implication of canonical wnt pathway and downstream tryptophan 2,3-dioxygenase (TDO2) signaling as critical to CDC therapeutic efficacy. This paved the way for the development of EVs from three engineered cell types. The first is IMEX, which derive from cardiosphere-derived cells engineered to be immortalized and deficient in the wnt-regulator, mest. The second is ASTEX, which derive from skin cells that overexpress the central wnt molecule beta-catenin and the cardiac lineage marker GATA4. The third are TDO2-EVs, which derive from fibroblasts engineered to overexpress TDO2. These engineered EVs have shown therapeutic efficacy in a variety of disease models, including myocardial infarction, heart failure, cardiomyopathy, Duchenne muscular dystrophy and SARS-CoV-2 infection. We have also developed tools for EV biology, including the identification of reference genes for expression analysis and methods of quantifying EV biodistribution.