中性粒细胞/单核细胞介导的药物输送系统靶向肾小管间质序贯修复急性肾损伤

如何突破肾小球滤过屏障(GFB)、靶向肾小管间质递送药物是急性肾损伤（AKI）研究领域的热点及难点。中性粒细胞（NE）和单核细胞（MN）在AKI的不同阶段被激活并向受损肾脏大量募集，能自主迁移穿过GFB，是递送药物进入肾小管间质的理想细胞载体。课题组前期工作发现，离体NE能装载脂质体并将其快速递送至炎症部位，而AKI后72小时是MN向受损肾脏趋化的最佳时机。在此基础上，提出在AKI急性期和修复期，分别利用循环NE/MN作为载体向肾小管间质进行药物递送的序贯治疗策略。本研究拟于AKI急性期，cRGD修饰的脂质体装载GSDMD抑制剂Stervioside靶向循环NE，被内吞后随其快速募集至肾小管间质，抑制炎性因子释放，减轻肾脏炎症；修复期，cRGD修饰的脂质体纳米粒装载Sgp130Fc，主动识别循环中MN，随其趋化至小管间质，阻断IL-6反式信号通路，减轻肾纤维化，序贯治疗促进肾损伤后修复。

Development of drug delivery systems that can overcome the glomerular filtration barrier (GFB) and target drugs to the renal tubulointerstitial is a recent hot topic for the treatment of acute kidney injury (AKI). Neutrophils and monocytes are activated and recruited to the damaged kidney at different pathological stages of AKI, migrating across the GBF, which confers them as ideal cell carriers for drug delivery. Our previous work demonstrated that neutrophils can load liposomes in vitro and rapidly deliver the liposomes to the remote inflammatory site after reinjection. However, the best time point for monocytes migrating to the inflammatory site is 72 hours after AKI. Therefore, in this project we proposed a new sequential treatment strategy which used blood circulating neutrophils and monocytes as cell carriers for drug delivery in the acute and repair stage of AKI, respectively. In the acute stage of AKI, cRGD-modified liposomes loaded with GSDMD inhibitor Stervioside were intended to target the circulation neutrophils and rapidly accumulated in the renal tubule interstitial, which resulted in inhibition of the release of inflammatory cytokines. During the AKI repair stage, cRGD-modified liposomes loaded with sgp130Fc actively recognized and targeted circulating monocytes, accumulating in the renal tubule interstitial. After the treatment, the hybrid system blocked IL-6 trans signaling pathway of interstitial cells, protected classic repair signaling pathway, and ultimately achieved a better effect on inflammation control and tissue repair.