Targeted tacrolimus delivery via manganese dioxide nanoparticles for mitigating acute allograft rejection in murine cardiac transplantation.

Abstract

Cardiac transplantation is the preferred treatment option for patients with chronic heart failure. However, acute rejection remains as a the significant challenge that leads to cardiac allograft dysfunction, resulting from immune system activation and reactive oxygen species (ROS) production by inflammatory cells. Current immunosuppressive regimens have limitations, such as systemic administration, toxicity, and inefficient inhibition of B cells, macrophages, and natural killer (NK) cells. Targeted immunosuppressant delivery via nanomaterials is a promising approach for sustained release within allografts, significantly enhancing drug efficiency. Manganese dioxide (MnO₂) possesses the characteristics of chemotaxis towards inflammatory sites, scavenging ROS, and facilitating drug transport. In this study, tacrolimus (FK506)-loaded MnO₂ nanoparticles (NPs) are synthesized via in-situ polymerization, using polydopamine (PDA) as an intermediate. The resulting FK506@MnO₂/PDA NPs exhibit excellent safety and cytocompatibility. This targeted delivery system significantly increases FK506 accumulation in murine cardiac allografts, effectively mitigating acute rejection and prolonging allograft survival. Furthermore, the mechanism by which FK506@MnO₂/PDA NPs alleviate acute rejection is investigated, validating that FK506 release inhibits T-cell activation while modulating the inflammatory environment by reducing oxidative stress and scavenging ROS. Fluorescence imaging demonstrates that FK506@MnO₂/PDA NPs exhibit prolonged retention and more pronounced accumulation in cardiac allografts compared with free FK506. This study presents a novel strategy for immunosuppressive therapy following cardiac transplantation, potentially improving allograft prognosis.