An engineered miniACE2 protein secreted by mesenchymal stromal cells effectively neutralizes multiple SARS-CoV- 2 variants in vitro.

SARS-CoV- 2 continues to evolve, producing novel Omicron subvariants through recombinant lineages that acquire new mutations, undermining existing antiviral strategies. The viral fitness and adaptive potential of SARS-CoV- 2 present significant challenges to emergency treatments, particularly monoclonal antibodies, which demonstrate reduced efficacy with the emergence of each new variant. Consequently, immunocompromised individuals, who are more susceptible to severe manifestations of COVID- 19 and face heightened risks of critical complications and mortality, remain vulnerable in the absence of effective emergency treatments. To develop translational approaches that can benefit this at-risk population and establish broader therapeutic strategies applicable across variants, we previously designed and engineered in silico miniACE2 decoys (designated BP2, BP9, and BP11). These decoys demonstrated promising efficacy in neutralizing Omicron subvariants. In this study, we leveraged the therapeutic potential of mesenchymal stromal cells (MSCs) for tissue repair and immunomodulation in lung injuries and used these cells as a platform for the secretion of BP2. Our innovative assays, which were conducted with the BP2 protein secreted into the culture supernatant of BP2-MSCs, demonstrated the potential for neutralizing SARS-CoV- 2, including Omicron subvariants. The development of these advanced therapeutic platforms holds significant promise for scalability to effectively mitigate the impact of severe COVID- 19, contributing to broader and more resilient treatment strategies against the evolving landscape of SARS-CoV- 2 variants.