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.