Lu Xinfeng, Hu Haitao, Zhou Yujie, Zhang Hui, Xie Chang, Sun Yiyang, Shao Zile, Tang Lin, Ren Yuhao, Chen Jun, Xu Xiao, Qiu Nasha, Guo Haijun
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou 310053, China.
Department of Medical Oncology, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou 221000 China.
Int J Pharm. 2025 Mar 15;672:125292. doi: 10.1016/j.ijpharm.2025.125292. Epub 2025 Jan 31.
Hepatic ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of patients undergoing surgery. Exosomes derived from mesenchymal stem cells (MSC-EXOs) are widely used and play a therapeutic role in hepatic IRI. However, natural exosomes lack liver-targeting ability and have low bioavailability. In this study, MSC-EXOs were simply modified with OPDEA-PCL or liver-targeting DSPE-PEG-Galactose, forming OPDEA-PCL-modified MSC-EXOs (OP-EXOs) or DSPE-PEG-Galactose-modified MSC-EXOs (GPEG-EXOs). In mouse hepatic IRI model, OP-EXOs and GPEG-EXOs both significantly reduced alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels in serum after hepatic IRI, alleviating liver injury. Transcriptomic and proteomic analyses showed that OP-EXOs and GPEG-EXOs reduced hepatic IRI by downregulating the expression of S100A8, S100A9, SELP, and ANXA2 in the liver following IRI. This study opens a new paradigm for the treatment of hepatic IRI using engineered MSC-EXOs with the potential to improve the prognosis of liver surgery.
肝缺血再灌注损伤（IRI）是影响手术患者预后的重要因素。间充质干细胞来源的外泌体（MSC-EXOs）被广泛应用，并在肝IRI中发挥治疗作用。然而，天然外泌体缺乏肝脏靶向能力且生物利用度低。在本研究中，MSC-EXOs用OPDEA-PCL或肝脏靶向性的DSPE-PEG-半乳糖进行简单修饰，形成OPDEA-PCL修饰的MSC-EXOs（OP-EXOs）或DSPE-PEG-半乳糖修饰的MSC-EXOs（GPEG-EXOs）。在小鼠肝IRI模型中，OP-EXOs和GPEG-EXOs均显著降低肝IRI后血清中的丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和乳酸脱氢酶（LDH）水平，减轻肝损伤。转录组学和蛋白质组学分析表明，OP-EXOs和GPEG-EXOs通过下调IRI后肝脏中S100A8、S100A9、SELP和ANXA2的表达来减轻肝IRI。本研究为使用工程化MSC-EXOs治疗肝IRI开辟了新的范例，有望改善肝脏手术的预后。
