Yan, Weiang (Institute of Cardiovascular Sciences, University of Manitoba )


Introduction: Allograft vasculopathy is an aggressive form of accelerated atherosclerosis that manifests uniquely in transplanted hearts, lungs, and kidneys. Activated blood vessel endothelial cells (ECs) stimulate alloreactive CD4+ and CD8+ T-lymphocytes to result in sustained inflammation. Transition metal carbides, MXenes, are an emerging class of nanomaterials that have recently been shown to have unique immunomodulatory properties. Here, we present the development and application of novel tantalum carbide MXene (Ta4C3Tx) quantum dots for in vivo immunomodulation and prevention of allograft vasculopathy.

Methodology: To infer mechanisms and to ensure reproducibility of results, detailed physicochemical characterization of Ta4C3Tx MXene quantum dots was performed using scanning/transmission electron microscopy, x-ray diffraction, and x-ray photoelectron spectroscopy. In vitro studies were carried out using co-cultures of human umbilical vein endothelial cells (HUVECs) with allogeneic peripheral blood mononuclear cells, and immunomodulatory function was assessed using flow cytometry. Mechanisms for immunomodulation was ascertained using quantitative real-time PCR. A rat aortic transplantation and allograft vasculopathy model was used for in vivo validation of safety and immunomodulatory function.

Results: A facile hydrofluoric acid-free protocol was rationally designed to synthesize a zero-dimensional MXene quantum dot (MQD) material. These MQDs were surface modified with high amounts of different functional groups. The average diameter of single particles was found to be about 3.5 nm. Using the in vitro co-culture system, we found that Ta4C3Tx MQDs interact with activated human ECs to reduce activation and pro-inflammatory Th1 polarization of allogeneic CD4+ lymphocytes. Furthermore, we showed that treatment with MQDs significantly increased endothelial surface expression of the T-cell co-inhibitory molecule PD-L1 and decreased expression of the costimulatory molecule CD86. Finally, when applied in vivo¸ our data suggested that treatment with MQDs could significantly reduce lymphocyte infiltration and preserve medial smooth muscle cell integrity within transplanted vessel segments.

Conclusion: These findings offer the promise of next generation Ta4C3Tx MQDs as a smart material for treatment of allograft vasculopathy and other inflammatory diseases. This research also opens the door to development of rationally designed Ta4C3Tx MXene quantum dot technologies for other immune-sensitive regenerative medicine applications.

Keywords: MXene, Immunomodulation, Nanomaterials, Regenerative Medicine


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