Broad-spectrum antiviral effect of MoringaA-loaded exosomes against IAV by mediating the GCN5-TFEB-autolysosome pathway

Influenza virus-induced viral pneumonia is a major threat to human health, and specific therapeutic agents for viral pneumonia are still lacking. MoringaA (MA) is an anti-influenza virus active compound isolated from Moringa seeds, which can inhibit influenza virus by activating the TFEB-autophagic lysosomal pathway in host cells. In this study, we obtained exosomes from M2-type macrophages and encapsulated and delivered MA (MA-Exos), and we investigated the efficacy of MA-Exos in antiviral and viral pneumonia in vivo and in vitro, respectively. In addition, we provided insights into the mechanism by which MA-Exos regulates TFEB-lysosomal autophagy by RNA sequencing. The MA-Exos showed broad-spectrum inhibition of IAV, and significant promotion of the autophagic lysosomal pathway. Meanwhile, we found that GCN5 gene and protein were significantly down-regulated in IAV-infected cells after MA-Exos intervention, indicating its blocking the acetylation of TFEB by GCN5. In addition, MA-Exos also significantly promoted autophagy in lung tissue cells of mice with viral pneumonia. MA-Exos can inhibit and clear influenza virus by mediating the TFEB-autophagy lysosomal pathway by a mechanism related to the down-regulation of histone acetyltransferase GCN5. Our study provides a strategy for targeting MA-Exos for the treatment of viral pneumonia from both antiviral and virus-induced inflammation inhibition pathways.