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

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.