PROJECT SUMMARY - Acute respiratory distress syndrome (ARDS) accounts for 10% of ICU admissions worldwide with a mortality as high as 46%. This incidence has risen dramatically in the last year due to the novel coronavirus (SARS-CoV-2) causing COVID-19, and ARDS is the leading cause of death in COVID-19 patients. In the United States, COVID-19 has infected over 30 million and killed 550,000 people already. Despite improvements in critical care and early detection of lung injury, the management of ARDS remains largely supportive, and while mechanical ventilation may provide the necessary life support, impaired pulmonary mechanics and subsequent ventilator induced lung injury (VILI) can impose a second insult that worsens outcomes. A range of systemic inflammatory insults, including trauma, sepsis, COVID-19, or local injury from toxic exposure, are associated with acute lung injury (ALI) and the development of ARDS, and result in alterations in lung compliance and lung fibrosis. While the etiology of ALI is multifactorial, a central pathogenic feature is a persistent activation of inflammation and oxidative stress. Following ALI, lung macrophages produce pro- inflammatory cytokines that result in the recruitment of additional inflammatory cells and the generation of reactive oxygen species (ROS). This pro-inflammatory state is regulated by key pro-inflammatory cytokines such as interleukin-6 (IL-6) and IL-8 which are stimulated by NFkB, a pro-inflammatory transcription factor. An additional layer of control of inflammation is through miR-146a, a regulatory microRNA that serves as a “molecular brake” on inflammation through inhibition of NFkB activation and downstream IL-6 and IL-8 expression. Ceria Therapeutics has developed a novel strategy to synergistically target both inflammation and oxidative stress. Novel cerium oxide nanoparticles (CNPs) have been designed and synthesized that possess ROS scavenging properties, conjugated with an anti-inflammatory miR-146a mimetic (CNP-miR146a), to target both ROS and the inflammatory response. In compelling preliminary data in a bleomycin-induced model of ALI, It was found that one-time administration of CNP-miR146a at the time of injury prevents inflammation and fibrosis and results in improved pulmonary mechanics. However, the ability to rescue lung injury and improve pulmonary mechanics after injury has occurred remain to be determined. Based on our hypothesis that CNP-miR146a will rescue ALI by reducing inflammation and oxidative stress, decrease fibrosis, and thus improve pulmonary mechanics, the objective of this proposal is to demonstrate the efficacy of our especially formulated form of CNP-miR146a for intratracheal delivery (CTX-002) to rescue existing ALI in two clinically relevant ALI animal models and to carry out a pilot safety assessment. The efficacy of CTX-002 in i) will be evaluated in a VILI-induced ALI model (Specific Aim 1) and ii) a two-hit model of live bacterial infection (S. aureus)...