Ultrasound‐Responsive Macrophage Biomimetic Phase‐Change Nanoparticles for Delivering miR‐126 Ameliorate Murine Heart Transplant Rejection

ABSTRACT Rejection following heart transplantation remains a significant challenge in the medical science. In addition to the immune response, the inflammatory response and microvascular endothelial damage can exacerbate rejection; however, current therapies focus primarily on the immune response. Numerous studies have confirmed that miR‐126 regulates vascular inflammation and promotes angiogenesis. To achieve the precise targeted delivery of miR‐126, macrophage biomimetic ultrasound phase‐change cationic nanoparticles carrying miR‐126 (miR‐126‐MCNPs) are synthesized. Incorporation of the macrophage membrane enhances the anti‐phagocytic and inflammatory targeting of nanoparticles, thereby prolonging the circulation time and promoting aggregation in the transplanted heart. Using ultrasound‐targeted microbubble destruction (UTMD), the perfluoropentane nanoparticle core undergoes a phase change in the ultrasound irradiation zone, allowing the targeted delivery of macrophage membranes and miR‐126, and significantly improving the transfection efficiency of the miR‐126. Consequently, anti‐inflammatory effects are achieved, such as inhibition of macrophage and CD3 ⁺ T cells infiltration, and alteration of M2‐type macrophage differentiation. In addition, this study demonstrates that the combination of miR‐126‐MCNPs with UTMD can alleviate the extent of vascular endothelial and interstitial fibrosis in transplanted hearts, increase angiogenesis, and improve microcirculation and cardiac function. This research provides a new strategy for the precision‐targeted therapy of cardiac transplant rejection.