Background <p>Corneal transplantation is a critical approach for some vision loss patients. However, the rejection of human organs severely affects the survival rate of the cornea. In addition, oral or intravenous medication against rejection may have side effects on patients, such as systemic immunosuppression. Therefore, a promising strategy for ocular local medication needs to be designed. On the basis of these findings, we constructed a novel platform, the mesenchymal stromal cell-coating high-oxygen permeable hydrogel lenses (MSCohi-O), which combines machinery and cells to achieve continuous drug delivery on the ocular surface to attenuate corneal transplant rejection.</p> Methods <p>Multiple in vitro experiments, including T-cell proliferation assay, cytokine secretion assay and relevant gene transcription assay have been performed to investigate the mechanisms of UCMSCs inhibiting inflammatory cells. The in vivo experiments using New Zealand rabbit as the corneal transplantation model have been conducted to verified the mechanism and potential of MSCohi-O rescuing transplanted cornea in recipients.</p> Results <p>Our in vitro experimental data investigated the mechanisms by which UCMSCs inhibit T cells and facilitate Treg cells through HLA-G5 modulation. In terms of efficacy, the data from the corneal transplantation model demonstrated that MSCohi-O protected the corneas from inflammation, prevented inflammatory cell infiltration in ocular tissues, inhibited proinflammatory cytokines, promoted Treg cell proportions, and ultimately prolonged the survival period of the transplanted corneas.</p> Conclusions <p>These findings addressed the rationale of MSCohi-O rescuing transplanted cornea in recipients, and suggested that MSCohi-O has great potential in managing the rejection of corneal transplantation clinically in the future.</p>