Cao Yuxin, Liu Xiaowei, Guo Chunjing, Yang Weili, Wang Xuemei, Wang Xinxin, Xu Haiyu, Wang Wenming, Liu Dandan, Zhang Jingwen, Cui Wenhao, Chen Yuxiu, Guo Xuan, Chen Daquan
Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China.
College of Marine Life Science, Ocean University of China, 5# Yushan 10 Road, Qingdao 266003, China.
J Control Release. 2025 Mar 10;379:59-76. doi: 10.1016/j.jconrel.2025.01.006. Epub 2025 Jan 8.
Cisplatin (Cis), a potent chemotherapeutic agent, often causes acute kidney injury (AKI), limiting its clinical efficacy. RONS flares at the AKI site are a key factor in its progression. In this study, leveraging the advantages of cell membrane-coated biomimetic nanocarriers, we developed a multifunctional biomimetic nanodelivery system nano-RONS-sacrificial agent for AKI treatment. Ferrostatin-1 (Fer-1) was conjugated with curcumin (Cur) via 4-carboxyphenylboronic acid (4-PBA) and fucoidan (Fuc) to construct a ROS-responsive nanodelivery system (FPPF@Cur), which was further coated with M2 macrophage membranes (M2M) to form the multifunctional biomimetic nano-RONS-sacrificial agent (M2FPPF@Cur) designed for targeted delivery of Cur to injured kidneys. M2FPPF@Cur demonstrated rapid accumulation in the injured kidneys with selective uptake and prolonged retention in injured kidneys, the ROS-responsive mechanism facilitated controlled drug release at the AKI site, reducing off-target effects and enhancing therapeutic efficacy, effectively scavenging RONS, reducing lipid peroxidation, and targeting GPX4 protein to inhibit "ferroptosis storm". It suppressed the expression of inflammation-related NF-κB/NLRP3 signaling pathway proteins and regulated the repolarization of macrophages from M1 to M2 phenotype to regulate inflammation. The results showed that injected M2FPPF@Cur specifically accumulated in the injured kidney and exerted good renoprotective effects ultimately preventing the progression of AKI.
顺铂（Cis）是一种强效化疗药物，常导致急性肾损伤（AKI），限制了其临床疗效。AKI部位的活性氧爆发是其病情进展的关键因素。在本研究中，我们利用细胞膜包覆的仿生纳米载体的优势，开发了一种用于AKI治疗的多功能仿生纳米递送系统——纳米活性氧清除剂。铁死亡抑制蛋白-1（Fer-1）通过4-羧基苯硼酸（4-PBA）和岩藻多糖（Fuc）与姜黄素（Cur）偶联，构建了一种活性氧响应性纳米递送系统（FPPF@Cur），该系统进一步包覆M2巨噬细胞膜（M2M），形成多功能仿生纳米活性氧清除剂（M2FPPF@Cur），旨在将Cur靶向递送至受损肾脏。M2FPPF@Cur在受损肾脏中显示出快速积累，具有选择性摄取并在受损肾脏中长时间滞留，活性氧响应机制促进了药物在AKI部位的可控释放，减少了脱靶效应并提高了治疗效果，有效清除活性氧，减少脂质过氧化，并靶向谷胱甘肽过氧化物酶4蛋白以抑制“铁死亡风暴”。它抑制了炎症相关的核因子κB/核苷酸结合寡聚化结构域样受体蛋白3信号通路蛋白的表达，并调节巨噬细胞从M1表型向M2表型的极化以调节炎症。结果表明，注射的M2FPPF@Cur特异性地在受损肾脏中积累，并发挥了良好的肾脏保护作用，最终防止了AKI的进展。
