MXenes are an emerging class of nanomaterials with significant potential for applications in nanomedicine. Amongst MXene technologies, titanium carbide (Ti3C2Tx) nanomaterials are the most mature and have received significant attention to tackle longstanding clinical challenges due to its tailored physical and material properties. Cardiac allograft vasculopathy is an aggressive form of atherosclerosis and a major cause of mortality among patients with heart transplants. Blood vessel endothelial cells (ECs) stimulate alloreactive T-lymphocytes to result in sustained inflammation. Herein, we report the first application of Ti3C2TxMXene nanosheets for prevention of allograft vasculopathy. MXene nanosheets interacted with human ECs and downregulated the expression of genes involved in alloantigen presentation, and consequently reduced the activation of allogeneic lymphocytes. RNA-Seq analysis of lymphocytes showed that treatment with MXene downregulated genes responsible for transplant-induced T-cell activation, cell-mediated rejection, and development of allograft vasculopathy. In anin vivorat model of allograft vasculopathy, treatment with MXene reduced lymphocyte infiltration and preserved medial smooth muscle cell integrity within transplanted aortic allografts. These findings highlight the potential of Ti3C2TxMXene in treatment of allograft vasculopathy and inflammatory diseases.