<p dir="ltr">Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses. Collectively, these functions suggest that IL-27 could be a promising therapeutic agent for acute respiratory distress syndrome (ARDS) and COVID-19, since both diseases are characterized by the dysregulation of the host’s immune response. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. In this approach, an IL-27-expressing plasmid was transfected into cells that serve as the gene therapy carriers. Adipose-derived mesenchymal stromal cells (ASCs) were chosen as the gene therapy carriers to take advantage of their homing ability to injury sites and their innate immunomodulatory functions. We tested the efficacy of IL-27-expressing ASCs in reducing inflammation in the context of ARDS through lipopolysaccharide (LPS)-induced models both <i>in vitro</i> and <i>in vivo</i>. Our results indicated that IL-27-expressing ASCs were able to reduce proinflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity. Additionally, we also modified IL-27 through the addition of an ACE2 targeting motif at the C-terminus. We hypothesized that this targeted form of IL-27 could reduce viral entry of SARS-CoV-2 spike pseudotyped lentivirus in vitro. While our results did not show significant changes in lentiviral entry, we recognize the limitations of our model and suggest that further investigation would be necessary to fully assess the potential of IL-27 as a therapeutic for COVID-19. In conclusion, our results showed promising potential for IL-27 cell-based gene therapy as a treatment for ARDS and COVID-19.</p>