Advancing immunomodulation in organ transplantation: the therapeutic potential of self-assembled rapamycin nanoparticles in allograft rejection

BACKGROUND: Transplant rejection remains a significant challenge, necessitating effective post-transplant interventions. Although rapamycin (RAPA) is a recognized immunosuppressant, its utility is limited by poor solubility and delivery efficiency. This study investigates a self-assembly strategy to enhance the solubility and efficacy of RAPA against graft rejection. METHODS: We synthesized soluble supramolecular rapamycin nanoparticles (sRNP) using reprecipitation, making RAPA injectable and stable in aqueous solutions. RESULTS: sRNP maintained sustained therapeutic concentrations, exhibited minimal toxicity, and notably enhanced graft survival compared to traditional oral RAPA administration. In murine allograft models, sRNP treatment effectively suppressed T cell proliferation in peripheral immune organs and the circulatory system. Detailed analyses revealed that sRNP significantly increased the population of naive T cells while decreasing effector T cells. Mechanistic investigations indicated that these effects were mediated by the enhanced recruitment of myeloid-derived suppressor cells (MDSC) and the promotion of regulatory T cells homing to lymph nodes. This led to reduced differentiation of Th1 and Th17 cells, along with a decrease in inflammatory cytokines, resulting in significantly prolonged graft survival compared to oral RAPA. Additionally, in a rat orthotopic liver transplantation model, intermittent low-dose sRNP treatment (1 mg/kg every other day intravenously) effectively inhibited T cell proliferation, reduced inflammatory cell infiltration, markedly extended graft survival, and significantly improved liver function. CONCLUSIONS: This study highlights sRNP's superiority over oral RAPA in managing allograft rejection by enhancing immune regulation, reducing T cell differentiation, and decreasing inflammation. These effects extend graft survival, underscoring sRNP's potential as an effective anti-rejection therapy.