Engineered Enucleated Mesenchymal Stem Cells Regulating Immune Microenvironment and Promoting Wound Healing
Zhengtai Chen1, Yang Zou1,2, Hanxiao Sun1
1Department of Plastic Surgery, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, 310000, China.
Abstract:
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.
Insights
Engineered enucleated mesenchymal stem cells, termed Cargocytes, effectively target and reduce inflammation in wound healing. This novel approach sustains interleukin-4 expression, improving macrophage function and promoting better wound repair.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Immunology
Background:
- Persistent inflammation from immune cell dysfunction hinders wound healing.
- Existing cytokine therapies have limitations like short half-lives and poor targeting.
Purpose of the Study:
- To develop a novel drug delivery vector for enhanced wound healing.
- To engineer enucleated mesenchymal stem cells for targeted and sustained therapeutic delivery.
Main Methods:
- Engineered enucleated mesenchymal stem cells (Cargocytes) using aptamer bioorthogonal chemistry.
- Modified cell membranes for targeting and loaded mRNA for sustained cytokine secretion.
- Targeted neutrophils' NETosis via DEK protein and sustained interleukin-4 (IL-4) expression.
Main Results:
- Cargocytes effectively reduced NETosis and prevented M1 macrophage polarization.
- Sustained IL-4 expression was achieved, overcoming limitations of free IL-4.
- Therapeutic effects were validated in murine and porcine wound models.
Conclusions:
- Engineered enucleated mesenchymal stem cells (Cargocytes) show promise as a wound healing therapy.
- This approach effectively modulates the wound immune microenvironment.
- Cargocytes offer a potential strategy for refractory wound treatment.
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