Phosphatidylserine nanobubbles: A macrophage-targeted ultrasound contrast agent - promising approach for the early detection of acute cardiac rejection.

BACKGROUND: Acute rejection (AR) continues to be a leading cause of mortality following heart transplantation. Endomyocardial biopsy, the current gold standard for monitoring, is limited by its invasiveness. Macrophage infiltration into the myocardial interstitium is an early hallmark of AR, targeting these specific cells offers a novel strategy for the accurate and stable noninvasive detection of rejection signals. To address this unmet clinical need, we developed a macrophage-targeted ultrasound contrast agent - phosphatidylserine nanobubbles (PS-NBs).

METHODS: PS-NBs were fabricated and their targeting ability toward macrophages was evaluated. Heterotopic heart transplantation models were established, and PS-NBs were injected for ultrasound molecular imaging. Signal intensity (SI) was compared between allografts and isografts. Imaging results were validated via H&E and CD68 immunohistochemical staining.

RESULTS: PS-NBs can effectively target macrophages. In allografts, PS-NBs exhibited significantly higher SI compared to control NBs. The SI of PS-NBs in the allograft group at seven days post-transplantation was stronger than that at three days, and significantly exceeded the SI observed in the isograft group. Crucially, a strong positive correlation was observed between PS-NB SI and macrophage infiltration density.

CONCLUSION: By specifically targeting macrophages that infiltrate in the myocardial interstitium, PS-NBs enable the highly accurate, stable, and noninvasive early detection of AR via ultrasound molecular imaging. This innovative strategy represents a key methodological improvement over current detection. Importantly, owing to their high in vivo biocompatibility, PS-NBs demonstrate considerable promise for future clinical translation.