The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19.

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), continues to be a major health concern. In search for novel treatment strategies against COVID-19, exosomes have attracted the attention of scientists and pharmaceutical companies worldwide. Exosomes are small extracellular vesicles, secreted by all types of cells, and considered as key mediators of intercellular communication and stem-cell paracrine signaling. Herein, we reviewed the most recent literature about the role of exosomes as potential agents for treatment, prevention, diagnosis, and pathogenesis of COVID-19. Several studies and ongoing clinical trials have been investigating the anti-inflammatory, immunomodulatory, and reparative effects of exosomes derived from mesenchymal stem/stromal cells for COVID-19-related acute lung injury. Other studies reported that exosomes play a key role in convalescent plasma therapy for COVID-19, and that they could be of use for the treatment of COVID-19 Kawasaki's-like multisystem inflammatory syndrome and as drug delivery nanocarriers for antiviral therapy. Harnessing some advantageous aspects of exosome biology, such as their endogenous origin, capability of crossing biological barriers, high stability in circulation, and low toxicity and immunogenicity, several companies have been testing exosome-based vaccines against SARS-CoV-2. As they carry cargos that mimic the status of parent cells, exosomes can be isolated from a variety of sources, including plasma, and employed as biomarkers of COVID-19. Lastly, there is growing evidence supporting the role of exosomes in COVID-19 infection, spread, reactivation, and reinfection. The lessons learned using exosomes for COVID-19 will help determine their efficacy and applicability in other clinical conditions.

Systematic review of extracellular vesicle-based treatments for lung injury: are EVs a potential therapy for COVID-19?

Severe COVID-19 infection results in bilateral interstitial pneumonia, often leading to acute respiratory distress syndrome (ARDS) and pulmonary fibrosis in survivors. Most patients with severe COVID-19 infections who died had developed ARDS. Currently, ARDS is treated with supportive measures, but regenerative medicine approaches including extracellular vesicle (EV)-based therapies have shown promise. Herein, we aimed to analyse whether EV-based therapies could be effective in treating severe pulmonary conditions that affect COVID-19 patients and to understand their relevance for an eventual therapeutic application to human patients. Using a defined search strategy, we conducted a systematic review of the literature and found 39 articles (2014-2020) that reported effects of EVs, mainly derived from stem cells, in lung injury models (one large animal study, none in human). EV treatment resulted in: (1) attenuation of inflammation (reduction of pro-inflammatory cytokines and neutrophil infiltration, M2 macrophage polarization); (2) regeneration of alveolar epithelium (decreased apoptosis and stimulation of surfactant production); (3) repair of microvascular permeability (increased endothelial cell junction proteins); (4) prevention of fibrosis (reduced fibrin production). These effects were mediated by the release of EV cargo and identified factors including miRs-126, -30b-3p, -145, -27a-3p, syndecan-1, hepatocyte growth factor and angiopoietin-1. This review indicates that EV-based therapies hold great potential for COVID-19 related lung injuries as they target multiple pathways and enhance tissue regeneration. However, before translating EV therapies into human clinical trials, efforts should be directed at developing good manufacturing practice solutions for EVs and testing optimal dosage and administration route in large animal models.