Dual ROS modulation by MnO ₂ -integrated collagen hydrogel enhances hiPSC-derived endothelial progenitor cell therapy for critical limb ischemia

Rationale: Cell therapy shows significant potential in treating ischemic diseases, such as critical limb ischemia. Endothelial progenitor cells (EPCs) are considered ideal candidates, but their clinical efficacy is often limited due to the scarcity of suitable sources and poor post-transplant survival. Human-induced pluripotent stem cell-derived EPCs (hiPSC-EPCs) offer a scalable and promising alternative. Additionally, injectable hybrid hydrogels can enhance cell retention and eliminate harmful components in the microenvironment, such as reactive oxygen species (ROS). However, conventional biomaterials are insufficient in mitigating intracellular oxidative stress induced by ischemia. Methods: -NPs on hiPSC-EPCs under oxidative stress was explored via immunofluorescence staining, transcriptome sequencing, Western blotting, enzyme-linked immunosorbent assay, mitochondrial function assays, and quantitative polymerase chain reaction. Results: -NPs provide a dual protective function by scavenging extracellular ROS and mitigating intracellular ROS via upregulation of MnSOD in transplanted hiPSC-EPCs. This comprehensive modulation of ROS significantly improves cell survival and functionality. Consequently, the protected hiPSC-EPCs robustly promote angiogenesis, restoring blood perfusion and improving limb salvage in critical limb ischemia. Conclusions: -based strategy represents a novel dual-action approach for enhancing cell therapy in ischemic diseases.