Engineered Enucleated Mesenchymal Stem Cells Regulating Immune Microenvironment and Promoting Wound Healing

Persistent excessive inflammation caused by neutrophil and macrophage dysfunction in the wound bed leads to refractory response during wound healing. However, previous studies using cytokines or drugs often suffer from short half‐lives and limited targeting, resulting in unsatisfactory therapeutic effects. Herein, the enucleated mesenchymal stem cell is engineered by aptamer bioorthogonal chemistry to modify the cell membrane and mRNA loading in the cell cytoplasm as a novel delivery vector (Cargocyte) with accurate targeting and sustained cytokine secretion. Cargocytes can successfully reduce NETosis by targeting the nuclear chromatin protein DEK protein with aptamers and sustaining interleukin (IL)‐4 expression to overcome the challenges associated with the high cost and short half‐life of IL‐4 protein and significantly prevent the transition of macrophages into the M1 phenotype. Therapeutic effects have been demonstrated in murine and porcine wound models and have powerful potential to improve wound immune microenvironments effectively. Overall, the use of engineered enucleated mesenchymal stem cells as a delivery system may be a promising approach for wound healing. In this study, bioorthogonal chemistry to function in the cell membrane and mRNA loading in the cell cytoplasm are combined to develop an engineered enucleated mesenchymal stem cells (Cargocyte). Cargocytes can modulate the two most important immune cells, neutrophils, and macrophages, by reducing NETosis and decreasing M1 macrophages phenotype polarization to regulate immune microenvironment and promote wound healing.