Acute kidney injury (AKI) caused by sepsis is a serious disease which mitochondrial oxidative stress and inflammatory play a key role in its pathophysiology. Ceria nanoparticles hold strong and recyclable reactive oxygen species (ROS)-scavenging activity, have been applied to treat ROS-related diseases. However, ceria nanoparticles can't selectively target mitochondria and the ultra-small ceria nanoparticles are easily agglomerated. To overcome these shortcomings and improve therapeutic efficiency, we designed an ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury.

Methods: Ceria nanoparticles were modified with triphenylphosphine (TCeria NPs), followed by coating with ROS-responsive organic polymer (mPEG-TK-PLGA) and loaded atorvastatin (Atv/PTP-TCeria NPs). The physicochemical properties, in vitro drug release profiles, mitochondria-targeting ability, in vitro antioxidant, anti-apoptotic activity and in vivo treatment efficacy of Atv/PTP-TCeria NPs were examined.

Results: Atv/PTP-TCeria NPs could accumulate in kidneys and hold a great ability to ROS-responsively release drug and TCeria NPs could target mitochondria to eliminate excessive ROS. In vitro study suggested Atv/PTP-TCeria NPs exhibited superior antioxidant and anti-apoptotic activity. In vivo study showed that Atv/PTP-TCeria NPs effectively decreased oxidative stress and inflammatory, could protect the mitochondrial structure, reduced apoptosis of tubular cell and tubular necrosis in the sepsis-induced AKI mice model.

Conclusions: This ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin has favorable potentials in the sepsis-induced AKI therapy.

败血症引起的急性肾损伤（AKI）是一种严重的疾病，线粒体的氧化应激和炎症在其病理生理中起关键作用。二氧化铈纳米粒子具有很强的可回收活性氧清除活性，已被用于治疗与ROS有关的疾病。但是，二氧化铈纳米粒子不能选择性地靶向线粒体，超小二氧化铈纳米粒子容易团聚。为了克服这些缺点并提高治疗效率，我们设计了一种针对ROS的纳米药物递送系统，该系统将靶向线粒体的氧化铈纳米粒子与阿托伐他汀相结合，用于急性肾脏损伤。

方法：用三苯膦（TCeria NPs）修饰二氧化铈纳米颗粒，然后用ROS反应性有机聚合物（mPEG-TK-PLGA）和负载的阿托伐他汀（Atv / PTP-TCeria NPs）涂覆。检查了Atv / PTP-TCeria NP的理化特性，体外药物释放曲线，线粒体靶向能力，体外抗氧化剂，抗凋亡活性和体内治疗功效。

结果：Atv / PTP-TCeria NPs可以在肾脏中积累，并具有较强的ROS响应释放药物的能力，TCeria NPs可以靶向线粒体以消除过量的ROS。体外研究表明Atv / PTP-TCeria NP表现出优异的抗氧化和抗凋亡活性。体内研究表明，在脓毒症诱发的AKI小鼠模型中，Atv / PTP-TCeria NPs可以有效降低氧化应激和炎症反应，可以保护线粒体结构，减少肾小管细胞凋亡和肾小管坏死。

结论：结合线粒体靶向二氧化铈纳米粒子与阿托伐他汀的这种ROS响应纳米药物递送系统在脓毒症诱发的AKI治疗中具有良好的潜力。