Therapeutic potential of hUCMSC-derived exosomes in modulating inflammation and immune response in...

COVID-19 has become a global pandemic, potentially leading to conditions like ARDS. The infection triggers severe inflammation and cytokine storms, damaging the lungs and other organs. MSCs and their derived exosomes are suggested as therapeutic options for reducing inflammation and modulating the immune response. This study evaluates the safety and efficacy of exosomes from umbilical MSCs in ARDS patients.

This randomized, double-blind, placebo-controlled pilot trial, conducted at Razi Hospital, Ahvaz, Iran, between October and December 2022, enrolled thirty hospitalized patients with COVID-19 and ARDS. Group A (n = 15) received a single intravenous dose of hUCMSC-Exos (5 × 10¹⁰ particles in 2-5 mL PBS), and Group B (n = 15) received a placebo (PBS), in addition to standard-of-care treatments. Clinical outcomes, inflammatory biomarkers (TNF-α, IL-6, CRP), and immune cell subsets (CD3⁺, CD4⁺, CD8⁺) were assessed at baseline and seven days after treatment. Categorical variables were reported as percentages, continuous variables as mean ± SD. Non-parametric tests and Quade ANCOVA were used for group comparisons and adjustment for baseline differences. Subgroup analyses based on Actemra use were performed to account for potential confounding effects on inflammatory and immune parameters.

The intervention group showed a significant reduction in inflammatory markers (TNF-α and CRP) and changes in immune cells, particularly CD3⁺ and CD4⁺. While no significant differences were found in mortality and hospitalization duration, the intervention group demonstrated improvements in inflammatory profiles and immune responses. The PRIEST score, assessing disease severity, was influenced by the intervention-time interaction, suggesting the therapeutic potential of hUCMSC-Exos in modulating disease progression. Subgroup analyses revealed that Actemra influenced IL-6 and lymphocyte counts, while TNF-α, CRP, and adaptive immune trends persisted in the exosome group, indicating effects beyond Actemra. Unequal Actemra distribution was accounted for to reduce bias.

The administration of hUCMSC-Exos was safe and associated with favorable trends, including reductions in TNF-α and CRP, as well as improvements in immune cell subsets (CD3⁺, CD4⁺, and CD8⁺). However, the independent effects of exosomes cannot be fully determined due to the concomitant use of therapies, including Actemra. The findings highlight the potential of exosome therapy in modulating inflammation and adaptive immune responses; however, larger, controlled trials stratified by concomitant treatments are required to confirm these preliminary results and clarify the therapeutic role of exosomes in COVID-19-associated ARDS.