Project Summary/Abstract “Mesenchymal Stem Cell Derived A1-Exosomes for Traumatic Brain Injury” This proposal will develop a novel therapy for severe traumatic brain injury (TBI), a condition that has devastating effects on the victims and creates a large burden over $55 billion per year on the US healthcare system. One of the distressing features of TBI is that after the acute phase, the patients gradually develop behavioral deficits. As a result, the disease is now considered as a chronic syndrome that involves a viscous cycle in which the initial inflammatory response is excessive so that it causes considerable injury to the brain and thereby triggers another round of lasting inflammation. Numerous anti-inflammatory agents have been tested for treating TBI, but none have yet been accepted as part of standard medical care. This proposal is based on earlier publications that demonstrated administration of mesenchymal stem/stromal cells produced beneficial effects in animal models of TBI (by MSCs), primarily through reducing inflammation, and the more recent observation by us and another lab that the beneficial effects of MSCs can be reproduced with small vesicles (exosomes) produced by MSCs. The proposed studies will establish the efficacy, safety, and mode of action of A1-exosomes in a mouse model of TBI. A1-exosomes are prepared from MSCs with a scalable protocol, which can be used as “off-the-shelf” reagents. We will compare the administration of A1-exosomes either intravenously or intranasally since we have recently found that intranasal administration of A1-exosomes dramatically reduces induced-neuroinflammation. If successful, the proposal will provide the basis for a novel clinical therapy for TBI and perhaps other diseases involving neuroinflammation such as Parkinsonism and Alzheimer’s disease.