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

Abstract

Acute respiratory distress syndrome (ARDS) represents a significant burden to the healthcare system, with ≈200 000 cases diagnosed annually in the USA. 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 nonviral delivery of anti‐inflammatory payloads to the inflamed/injured lung. The 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. Significant attenuation is observed in tissue damage, proinflammatory cytokine secretion, macrophage activation, influx of protein‐rich fluid, and neutrophil infiltration into the alveolar space as early as 6 h post‐eEVs treatment. Additionally, metabolomics analyses show that eEV treatment causes significant changes in the metabolic profile of inflamed lungs, driving the 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 nonviral delivery of anti‐inflammatory genes/transcripts.

ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer

“…Engineered EVs were derived from primary mouse embryonic fibroblast (MEF) cultures co-transfected with expression plasmids for miR-146a, Glut1 , and ICAM-1 , following methods previously published by us and others. 28–30,55–57 Control EVs were obtained by transfecting cells with sham/empty plasmids (Fig. 2A).…”

“…27 Previous studies have shown the production of engineered EVs, after the manipulation of donor cells, decorated with ligands for targeted delivery of specific molecular cargo for different applications. 28–30 Additionally, EVs circumvent many of the practical and translational barriers that are characteristic of other delivery systems by offering flexibility in cargo size, unlike viral vectors that have inherent capsid size restrictions, 29 and improved transfection efficiency and low toxicity compared to synthetic carriers. 25 However, EVs derived from progenitor/stem cell populations still face several challenges limiting their clinical translation, such as an increased risk of tumorgenicity, immunogenicity, and limited cell sources.…”

“…25 However, EVs derived from progenitor/stem cell populations still face several challenges limiting their clinical translation, such as an increased risk of tumorgenicity, immunogenicity, and limited cell sources. 31 Nevertheless, our group's recent studies suggest that EVs derived from more readily available cell sources, like allogeneic fibroblasts, 28,30 may hold the potential to overcome these obstacles due to their reduced immunogenicity and current use in clinical applications, 30 highlighting them as a promising cell source for EV-based therapeutics.…”

Akkermansia muciniphila attenuated lipopolysaccharide-induced acute lung injury by modulating the gut microbiota and SCFAs in mice

“…30,31 Thus, inflammatory cell influx, cytokine release, and protein leakage are key events in ALI. 32,33 Surprisingly, we discovered that A. muciniphila decreased the levels of inflammatory mediators and improved permeabilization of the alveolocapillary barrier. Our findings were consistent with the finding that inhibiting inflammation contributed to mitigation of pulmonary tissue injury.…”

“…Our findings were consistent with the finding that inhibiting inflammation contributed to mitigation of pulmonary tissue injury. 25,33 Local tissue injury and microbial infection activate immunologic cells, which produce inflammatory cytokines, such as IL-1β and IL-6, causing more severe mucosal injury. 34 IL-6 was reported to drive the differentiation of Th17 cells by activating STAT3, thereby enhancing neutrophil recruitment and reducing the bacterial burden.…”