A Novel Secretome Rewrites the Immune Response in Viral Acute Respiratory Distress Syndrome

Abstract Background Hyperinflammatory syndromes such as viral acute respiratory distress syndrome (ARDS) demand immunotherapies that are safe and effective at suppressing cytokine storm. As a novel treatment for ARDS, PRS CK STORM is proposed as a next-generation cell-free secretome derived from co-cultures of M2 macrophages and mesenchymal stromal cells. Methods We performed a double-blind, randomized controlled trial to test the effects of PRS CK STORM in K18-hACE2 transgenic mice infected intranasally with 10 5 PFU of SARS-CoV-2 BE.1.1. This was complemented by a mechanistic analysis of this secretome using transcriptomic and COX2 enzymatic activity studies, as well as a compositional analysis of its proteomic and miRNA profile. Results In a lethal SARS-CoV-2 ARDS mouse model, PRS CK STORM significantly improved lung histopathology to a degree on par with corticosteroids, while stimulating angiogenesis in damaged lung tissue. Early and late cytokine profiling showed marked reductions in IFN-γ. In response to PRS CK STORM treatment, transcriptomic analyses in inflamed macrophages revealed robust downregulation of key proinflammatory drivers (MyD88, TRAF6, IKK2, NF-κB, COX2). In vitro enzymatic assays confirmed potent, dose-dependent inhibition of COX2, with high inter-batch reproducibility. A compositional analysis revealed this secretome to be rich in anti-inflammatory miRNAs, immune-modulating proteins, and regenerative factors. Conclusions PRS CK STORM operates as a multi-target immune recalibrator, enabling broad downregulation of pathological inflammation while promoting tissue repair. Its off-the-shelf, GMP-manufactured format ensures reproducibility and scalability, offering a novel resolution pharmacology approach for cytokine storm syndromes originated from ARDS and beyond.