Acute respiratory syndrome distress syndrome (ARDS) is the most severe complication of coronavirus disease 2019 (COVID-19), caused by a betacoronavirus, SARS-CoV-2. Patients with ARDS secondary to COVID-19 often require mechanical ventilation support, and unfortunately present a mortality of more than 20% (23,24,25). Mesenchymal stromal cell (MSC) therapies have been under consideration for treating a wide range of inflammatory conditions due to their immunomodulatory capacity, hypoimmunogenic status, and excellent safety profile. MSC therapy is now gaining additional attention as a potential approach to suppressing the cytokine storm induced by COVID-19 (28), as the morbidity of COVID-19 is associated with strong inflammatory response to SARS-CoV-2 infection, which induces swelling of the lung, infiltration of inflammatory cells, and non-cardiogenic pulmonary edema that limits gas exchange in the distal lung. At this time, over 20 clinical trials for treating COVID-19 with MSCs have been registered with ClinicalTrials.gov. Intravenous administration of allogeneic MSCs in a small group of COVID-19 patients in China [11] indicated that the systemic inflammation was markedly suppressed and followed by improved clinical symptoms. The study proposed here as a 1-year supplement to our P41 EB27062 grant is designed to leverage, extend and combine our methodologies for derivation of immunomodulatory MSCs [19,20] and whole-lung bioengineering [3,4,6-9,14,15] towards establishing an effective modality for treating and preventing the progression of COVID-19 ARDS. Specifically, we aim to address three critical questions that would lead to the effective use of MSCs with a simplified regulatory path, to prevent and treat the COVID-19 ARDS. Question 1: Can the ability of MSCs to suppress the cytokine storm preceding ARDS be enhanced by cell priming with hypoxia and interferon-γ? Question 2: Given that the MSCs act largely by the factors they produce, would exosomes from primed MSCs simililarly have enhanced immunomodulatory effects? Question 3: Can MSC-exosomes be effectively used during the early stages of ARDS and delivered by nebulization directly into the lung? To this end, we will pursue three specific aims in an integrated fashion, by extending and leveraging the technologies developed in the parent grant, and using our highly translational swine model of ARDS to establish a novel ARDS treatment.