Diabetes mellitus (DM) leads to a 3-4 fold higher risk of experiencing ischemic stroke. Stroke in type two DM (T2DM) patients and in animal models increases vascular and white matter (WM) damage in the ischemic brain, and stroke in T2DM patients has a distinct clinical pattern and a poor prognosis compared to non-DM stroke. Exosomes (Exo), are active nano size biological lipid containers, which transport regulatory genes and proteins between cells and form a major biological communication conduit, facilitating a plethora of biological responses. The regulatory molecules contained in the exosome include microRNAs (miRs), which regulate gene translation and play primary roles in mediating a vast range of biological functions. MicroRNA-126 (miR- 126) is an angiogenic microRNA and primarily expressed in endothelial cells (EC). Specific conditional knockout of EC miR-126 (miR-126EC-/-) mice have significantly worse functional outcome after stroke as well as decreased brain miR-126 and ATP-binding cassette transporter A1 (ABCA1) expression. Exosomes derived from EC (EC-Exo) have a high level of miR-126. Based on our robust preliminary data, in this pioneering study, we propose that treatment of stroke with EC-Exo will enhance neurorestorative effects after stroke in T2DM mice, possibly, via the miR-126/ABCA1 signaling pathway. This application includes three Aims. Aim-1: To test the therapeutic effects of EC-Exo on cerebral ischemic stroke in adult male and female T2DM mice. Aim-2: To evaluate whether miR-126 mediates EC-Exo treatment induced neurorestorative effects, we will evaluate the therapeutic effects of treatment of stroke in specific conditional knockout of EC miR-126 (MiR-126EC-/-) and in non-miR-126 knockout control (miR-126fl/fl) T2DM mice with EC-Exo derived from miR-126EC-/- brain ECs (miR-126EC-/-EC-Exo) or EC-Exo derived from wild type miR-126fl/fl brain ECs (miR-126fl/fl-EC-Exo) on vascular and axonal/WM remodeling and neurological and cognitive functional outcome. Aim-3: To test whether ABCA1, an indirect target of miR-126, contributes to EC-Exo treatment induced neurorestorative effects after stroke in adult male T2DM mice, mice with specific knockout of brain ABCA1 (ABCA1-B/-B) and WT ABCA1 knockout control (ABCA1fl/fl) mice will be employed. In this application, we are the first to propose that, generation of miR-126 encapsulated in EC-Exo contributes to its robust therapeutic restorative effects and that miR-126/ABCA1 pathway mediates EC-Exo-induced neurovascular and WM remodeling, and thereby improves stroke neurological and cognitive functional recovery in T2DM mice. This proposal is highly clinically relevant and if successful, will significantly impact the treatment of diabetic stroke, and possibly all stroke patients.