Extracellular vesicles derived from MSCs carrying dexamethasone alleviate inflammatory damage in septic mice

Sepsis is a life-threatening condition resulting from an uncontrol immune response to infection. Current treatment options remain limited and often ineffective, highlighting the need for supportive anti-inflammatory and immunomodulatory strategies. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) can be a good supportive candidate because of their immunomodulatory and drug-delivery properties. Dexamethasone (Dex), a commonly used anti-inflammatory agent, was assessed in this study alongside MSC-EVs to evaluate their combined anti-inflammatory, immunomodulatory, and tissue-repairing effects in septic mice. Hence, we designed two combinations of EVs and Dex: a simple mixture of EVs and Dex (Dex + EV), and EVs loaded with Dex (L-Dex-EVs). Then the cecal ligation and puncture CLP-induced sepsis C57BL/6 mice were grouped based on treatment: 1) EVs, 2) Dex, 3) Dex + EV, and 4) L-Dex-EVs, as well as 5) CLP and 6) Sham groups as control. Tissue samples, bronchoalveolar lavage (Molinaro et al.) fluid, and serum were collected following the treatments to investigate inflammation and tissue damage-related factors. The findings indicated that both combined treatments resulted in decreased levels of IL-6 and TNF-α, while increasing IL-10 and TGF-β levels in BAL fluid and serum. Furthermore, the expression of HMGB1, NLRP3, caspase-1, and caspase-3 was downregulated in lung tissue, whereas iNOS expression was decreased and Arg-1 expression was upregulated in the spleen. Histological analysis (H&E staining) and serum biomarkers' assessments revealed diminished inflammation and improved tissue repair in the groups receiving combined treatments. These findings suggest that the combination of MSC-EVs and Dex, exerting synergistic effects that attenuate inflammatory responses and promote tissue regeneration in septic mice.