Figure 4.

Circulating extracellular vesicles carry immunomodulatory miRNAs in SARS-CoV-2. EVs can be divided into exosomes, microvesicles, and apoptotic bodies according to their diameter. SARS-CoV-2 viruses invade cells through ACE2 receptors and EVs enter cells through various pathways, including membrane fusion, receptor-mediated uptake, and active endocytosis. After EV internalization, through the endolysosomal pathway, the lipidic bilayer of the EVs are degraded and their cargo miRNAs are released in the cell cytoplasm allowing the performance of each cargo-specific action. EVs carry miRNAs that negatively regulate viral infection, inhibiting viral replication by restricting viral protein levels or nucleic acid components during reverse transcription. MiR-92a-3p, miR-103a-3p, miR-181a-5p, miR-26a-5p, and miR-23a-3p can block SARS-CoV-2 RNA replication, and miR-181A-5p can regulate the release of pro-inflammatory cytokines and reduce the inflammatory response. Similarly, exosomal miRNAs (miR-7-5p, miR-24-3p, miR-145-5p, and miR-223-3p) can also directly inhibit S protein expression and SARS-CoV-2 replication. In addition, exosomes miR-148a and miR-590, which directly target ubiquitin-specific peptidase 33 (USP33) and interferon regulatory factor 9 (IRF9), respectively, effectively modulated pro-inflammatory gene expression profiles (TNF-α, NF-κB, and IFN-β), leading to severe neuroinflammation in the CNS. Conversely, viruses can also influence the loading mechanism of EVs in infected cells to modulate the host immune response by regulating the qualitative and quantitative changes in the delivery of proteins or nucleic acids.