Mesenchymal stem cell derived exosomes mitigate COVID-19 cytokine storm via Annexin A1 and TGF-β mediated MAPK pathway inhibition

• MSC-Exos significantly downregulate MAPK pathway genes (MEKK1, MEKK2, MEKK3) and reduce phosphorylation of JNK1, p38, and ERK1/2, thereby mitigating the COVID-19 cytokine storm. • In silico docking reveals strong interactions between exosomal proteins (Annexin A1, TGF-β) and MAPK components, suggesting a mechanistic basis for immunomodulation. • In vivo validation in a Syrian hamster model shows reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and improved lung histopathology, indicating therapeutic potential for ARDS. • MSC-Exos offer a promising cell-free adjunctive therapy for severe COVID-19, potentially overcoming limitations of direct cell-based treatments.