Engineered Extracellular Vesicles Derived from Dermal Fibroblasts Attenuate Inflammation in a Murine Model of Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) represents a significant burden to the health care system, with approximately 200,000 cases diagnosed annually in the US. ARDS patients suffer from severe refractory hypoxemia, alveolar-capillary barrier dysfunction, impaired surfactant function, and abnormal upregulation of inflammatory pathways that lead to intensive care unit admission, prolonged hospitalization, and increased disability-adjusted life years. Currently, there is no cure or FDA-approved therapy for ARDS. This work describes the implementation of engineered extracellular vesicle (eEV)-based nanocarriers for targeted non-viral delivery of anti-inflammatory payloads to the inflamed/injured lung. Our results show the ability of surfactant protein A (SPA) functionalized IL-4- and IL-10-loaded eEVs to promote intrapulmonary retention and reduce inflammation, both in vitro and in vivo. We observed significant attenuation in tissue damage, proinflammatory cytokine secretion, macrophage activation, influx of protein-rich fluid and neutrophil infiltration into the alveolar space as early as 6 hours post-eEVs treatment. Additionally, metabolomics analyses showed that eEV treatment caused significant changes in the metabolic profile of inflamed lungs, driving secretion of key anti-inflammatory metabolites. Altogether, these results establish the potential of eEVs derived from dermal fibroblasts to reduce inflammation, tissue damage, and the prevalence/progression of injury during ARDS via non-viral delivery of anti-inflammatory genes/transcripts. This article is protected by copyright. All rights reserved.