Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects

Abstract

The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19.

Long COVID: The Nature of Thrombotic Sequelae Determines the Necessity of Early Anticoagulation

“…EVs are classified into three types: exosomes, microparticles (MPs), and apoptotic bodies. Their function is to transport cargo to nearby or distant cells to help maintain their physiological state ( Karn et al., 2021 ). EVs share structural similarities with viruses, such as small size, biogenesis mechanism and cell entry mechanism, etc.…”

COVID-19 inflammation and implications in drug delivery

“…EVs, including exosomes (size:30–150 nm), microvesicles (size:150–1000 nm), and apoptotic bodies (random size >1000 nm), are nucleus-free membranous structures charged with biocompounds (nucleic acids, proteins, and lipids), secreted by various kinds of cells in vivo as intercellular communication mediators, but also in vitro in response to external stimulus. EVs inherit many features from their source cells making them promising DDS and therapeutic candidates for many diseases, particularly their smallest subtype exosomes [ [112] , [113] , [114] , [115] ].…”

“…The therapeutic effects of MSCs are partly mediated by their paracrine activity and especially by their extracellular vesicles. MSC-derived exosomes contain a panel of proteins, lipids, and microRNAs such as miR-124-3p, 21-5p, 146a, 34a, 122, 124, and 127 involved in suppressing inflammation and pulmonary cell apoptosis, enabling them to exert similar immunomodulatory and regenerative potential as their mother cells [ 113 , 178 ]. Moreover, MSC-derived exosomes may offer several advantages over MSCs, such as higher stability, lower immunogenicity, and the ability to bypass physiological barriers [ 179 ].…”

Extracellular Vesicles, New Players in Sepsis and Acute Respiratory Distress Syndrome

“…The paracrine effect of MSCs can realize the transfer of nucleic acids and proteins between damaged cells, and has been shown to have a beneficial effect on sepsis, thereby reducing sepsis-related morbidity and mortality ( Mei et al., 2010 ; Weil et al., 2011 ; Alcayaga-Miranda et al., 2017 ). MSC-derived EVs can transfer mitochondria, proteins, mRNA and miRNAs via binding to the CD44 receptor on macrophages, which can inhibit cytokine storms but promote the production of anti-inflammatory cytokines, ATP and oxidative phosphorylation, thereby contributing to the recovery of lung injury ( Karn et al., 2021 ). EVs released by human umbilical cord mesenchymal stem cells (huc-MSCs) inhibit the expression of inflammatory cytokine by transferring miR-377-3p ( Wei et al., 2020 ).…”