Sun Ruiqi, Liang Zhi, Wang Ning, Chen Xiaona, Zhao Jialing, Tang Hong, Zhao Wentao, Wang Hangxiang, Zheng Shusen, Song Penghong, Xie Haiyang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, 79, Qingchun Road, Hangzhou, 310003, China.
NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS; Key Laboratory of Organ Transplantation; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, 79, Qingchun Road, Hangzhou, 310003, Zhejiang Province, China.
J Nanobiotechnology. 2025 Jun 5;23(1):418. doi: 10.1186/s12951-025-03498-5.
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.
We synthesized soluble supramolecular rapamycin nanoparticles (sRNP) using reprecipitation, making RAPA injectable and stable in aqueous solutions.
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.
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.
移植排斥仍然是一个重大挑战，需要有效的移植后干预措施。尽管雷帕霉素（RAPA）是一种公认的免疫抑制剂，但其效用因溶解度差和递送效率低而受到限制。本研究探讨了一种自组装策略，以提高RAPA对移植物排斥的溶解度和疗效。
我们采用复沉淀法合成了可溶性超分子雷帕霉素纳米颗粒（sRNP），使RAPA可注射并在水溶液中稳定。
与传统口服RAPA给药相比，sRNP维持了持续的治疗浓度，毒性极小，并显著提高了移植物存活率。在小鼠同种异体移植模型中，sRNP治疗有效抑制了外周免疫器官和循环系统中的T细胞增殖。详细分析表明，sRNP显著增加了幼稚T细胞的数量，同时减少了效应T细胞。机制研究表明，这些作用是由髓源性抑制细胞（MDSC）募集增加和调节性T细胞归巢至淋巴结的促进介导的。这导致Th1和Th17细胞分化减少，炎症细胞因子减少，与口服RAPA相比，移植物存活时间显著延长。此外，在大鼠原位肝移植模型中，间歇性低剂量sRNP治疗（每隔一天静脉注射1mg/kg）有效抑制了T细胞增殖，减少了炎症细胞浸润，显著延长了移植物存活时间，并显著改善了肝功能。
本研究强调了sRNP在通过增强免疫调节、减少T细胞分化和减轻炎症来管理同种异体移植排斥方面优于口服RAPA。这些作用延长了移植物存活时间，突出了sRNP作为一种有效抗排斥疗法的潜力。
