Related to Fig.3 Additional File: Physique S3Representative flow cytometry of Treg cells overlaid on total CD4+T cells. against SARS-CoV-2 contamination. Transplanted engineered clinical-grade MSCs effectively delivered the SARS-CoV-2 antibodies to the lung, and the immune hyperresponsiveness caused by 6-Thioguanine COVID-19 was coordinated by MSC clones through inhibiting the differentiation of CD4 + T cells into Th1 and Th17 subpopulations. == Conclusions == Our data suggested that engineered clinical-grade MSCs secreting effective neutralizing antibodies as cellular production machines had the potential to combat SARS-CoV-2 infection, which provided a new avenue for effectively treating the older and immunocompromised COVID-19 patients. == Supplementary Information == The online version contains supplementary material available at 10.1186/s13578-023-01099-z. Keywords:MSC, COVID-19, Anti-SARS-CoV-2 antibodies, Gene modification, mAbs delivery platform == Background == Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are responsible for the ongoing pandemic of COVID-19, which has imposed a heavy burden on global health and caused the deaths of millions of individuals worldwide (https://covid19.who.int). International data have shown that three-dose vaccination continue to be effective to neutralize the Omicron variant and reduce the frequency of severe outcomes [1,2]. However, vaccination coverage remains low in older individuals (> 65 years old) due to vaccination restriction of some underlying diseases, and older people have high risk of experiencing severe or long-term symptoms associated with omicron variants, and require hospitalization, with increased rates of fatality [35]. Thus, developing effective treatment for severe cases, especially the elderly is usually of global importance. Many studies have illustrated the clinical safety and efficacy of monoclonal antibodies (mAbs) therapies for COVID-19 patients. It is worth noting that the main target populations for such antibody therapy include those aged over 65 with comorbidities and immunocompromised individuals. The mAb-based approaches can reduce the severity and mortality of these populations [68]. To date, several mAb therapies have been applied in clinical practice, such as bamlanivimab (LY-CoV555) and etesevimab [9]. However, new Omicron subvariants BA.2 and BA.4/5 have become dominant worldwide. These new subvariants carrying further mutations raise concerns that they may further evade mAbs. Currently, only bebtelovimab (LY-CoV1404) can still be successfully used in the fight against the Omicron [10]. It is noteworthy that a recent study revealed that antibodies elicited by vaccination had greater binding 6-Thioguanine breadth than antibodies elicited by natural infection, which means that SARS-CoV-2 mutations have less impact on vaccine-elicited antibodies [11]. Over the past decades, mesenchymal stromal cell (MSC) therapies have progressed from a skeptical idea to clinical reality. The safety and efficacy of MSC therapies have been exhibited in a variety of clinical trials, such as acute respiratory distress syndrome (ARDS) and immune-mediated inflammatory diseases [1215]. 6-Thioguanine Notably, several clinical data have shown that MSCs therapies can improve clinical outcomes of COVID-19 patients [16,17]. MSCs can regulate the inflammatory environment and reduce the occurrence of cytokine storm, which were the major causes of organ damage that lead to the progression of severe COVID-19 [18]. In addition, MSCs have been used as a suitable gene therapy vectors for in vivo delivery of any therapeutic molecules, such as human soluble tumor necrosis factor receptor II (hsTNFR), interleukin-10 (IL10), and basic fibroblast growth factor (BFGF), demonstrating a promising therapeutic efficacy of genetically engineered MSCs in rheumatoid arthritis (RA) and spinal cord injury (SCI) [1921]. To date, engineered MSCs that encode various mAbs have shown improved therapeutic efficacy and kinetics compared with direct application of the same antibody [22,23]. However, no study examines the use of engineered MSCs as autonomous cellular machines for the SARS-CoV-2-specific neutralizing antibodies production to combat SARS-CoV-2 infection. Therefore, we posit that this utility of engineered MSCs as the SARS-CoV-2 neutralizing mAbs delivery platform could substantially improve the clinical outcomes of vulnerable populations by modulating the COVID-19 related immune responses and reducing SARS-CoV-2 entry and replication in vivo. In this study, we constructed various recombinant plasmids encoding corresponding SARS-CoV-2 antibodies (infection-elicited antibodies 215 and LY-CoV1404 as well as vaccine-elicited antibody XGv347) and electroporated these plasmids into clinical-grade MSCs to investigate their feasibility and efficacy to Goat polyclonal to IgG (H+L)(HRPO) treat SARS-CoV-2 infection. We successfully screened two stable engineered MSCs clones secreting specific mAbs against Omicron subvariants, revealed by pseudovirus neutralization assay. Our study indicated the engineered MSCs as neutralizing mAbs delivery platform could coordinate immune hyperresponsiveness and directly neutralize virus in acute SARS-CoV-2 patients, providing a robust basis for the older or vulnerable individuals with COVID-19. == Results == == Engineered human clinical-grade MSCs expressing SARS-CoV-2-neutralizing mAbs == The publicly available sequences of three SARS-CoV-2-neutralizing mAbs,.