Macrophage-Mimicking Biomimetic Microbubbles for Early Ultrasound Molecular Imaging of Acute Rejection in Heart Transplantation

Acute rejection (AR) is an important cause of heart graft injury and failure. Accurate diagnosis of AR is essential to achieving early intervention and improving the prognosis of patients. Current clinical monitoring of AR requires repeated invasive endocardial biopsies, and there is an urgent need to develop a noninvasive diagnostic technique. As antigen-presenting cells, macrophages play an important role in adaptive immunity, such as the early activation of T cells in AR, and are considered to be key drivers of AR. Macrophage membrane biomimetic microbubbles (MB-Mφ) inherit a variety of functional proteins from the macrophage membranes. They can recognize and target the inflammatory site in the heart and use ultrasound imaging signals to determine the inflammatory progression of AR. This "ultrasound probe" can be regarded as a dynamic tracer and visualization tool for the behavior of macrophages. MB-Mφ prepared in this study showed superior stability and ultrasound imaging performance, and its ability to adhere to inflammatory vascular endothelial cells was significantly better than that of ordinary microbubbles (MB). In the rat allograft model, the signal intensity of the MB-Mφ group was significantly higher than that of the ordinary microbubbles group. In addition, after injection of MB-Mφ, the signal intensity in the allograft group was significantly higher than that in the isograft group, and the pathological results confirmed that the signal intensity of MB-Mφ was positively correlated with the number of macrophages infiltrating the transplanted heart and the progression of AR. These findings indicate that macrophage membrane biomimetic microbubbles can mimic the inflammatory chemotactic behavior of macrophages and noninvasively detect AR in heart transplantation, which provides a new molecular imaging tool for early diagnosis.