Yoon Young Chul, Lee Dosang, Park Jung Hyun, Kim Ok-Hee, Choi Ho Joong, Kim Say-June
Pancreas. 2025 Mar 1;54(3):e210-e220. doi: 10.1097/MPA.0000000000002419. Epub 2024 Nov 26.
This study assessed the anticancer potential of genetically modified exosomes engineered to express CD133-binding peptides on their surface and carry PD-L1 siRNA for the treatment of murine model of metastatic pancreatic cancer.
CD133-targeting exosomes (tEx) were generated by harvesting conditioned media from adipose-derived stem cells (ASCs) that had undergone transformation using pDisplay vectors encoding CD133-binding peptide sequences. Subsequently, siPD-L1-loaded CD133-targeting Exosomes, referred to as tEx(s), were created by incorporating PD-L1 siRNA into the tEx using Exofect kit.
tEx(s) demonstrated superior targetability compared to other materials, including Ex, Ex(p), and tEx. This was substantiated by higher total radiant efficiency (TRE) observed in metastatic liver and pancreatic tissues following intravenous administration of tEx(s) ( P < 0.05). Furthermore, the intravenous delivery of tEx(s) resulted in the most pronounced upregulation of proapoptotic markers (BIM and c-caspase 3) and the least downregulation of the antiapoptotic markers (Mcl-1 and Bcl-xL), which has been demonstrated in various methods, including real-time polymerase chain reaction, western blot analysis, and immunohistochemistry in the metastatic lesions in the livers ( P < 0.05).
PD-L1 siRNA-loaded CD133-tEx demonstrated remarkable anticancer efficacy, characterized by specific binding to CD133-positive pancreatic cancer cells and suppression of PD-L1 expression within these cells.
本研究评估了经基因改造的外泌体的抗癌潜力，这些外泌体经工程改造后在其表面表达与CD133结合的肽，并携带PD-L1小干扰RNA（siRNA）用于治疗转移性胰腺癌的小鼠模型。
通过收集来自脂肪来源干细胞（ASC）的条件培养基来生成靶向CD133的外泌体（tEx），这些ASC已使用编码与CD133结合肽序列的pDisplay载体进行了转化。随后，通过使用Exofect试剂盒将PD-L1 siRNA掺入tEx中，创建了负载siPD-L1的靶向CD133的外泌体，称为tEx(s)。
与其他材料（包括Ex、Ex(p)和tEx）相比，tEx(s)表现出更高的靶向性。在静脉注射tEx(s)后，转移性肝脏和胰腺组织中观察到更高的总辐射效率（TRE），这证实了这一点（P < 0.05）。此外，tEx(s)的静脉给药导致促凋亡标志物（BIM和c-半胱天冬酶3）的上调最为明显，抗凋亡标志物（Mcl-1和Bcl-xL）的下调最少，这已通过多种方法得到证实，包括实时聚合酶链反应、蛋白质免疫印迹分析以及肝脏转移病变中的免疫组织化学（P < 0.05）。
负载PD-L1 siRNA的CD133-tEx表现出显著的抗癌疗效，其特征是与CD133阳性胰腺癌细胞特异性结合并抑制这些细胞内的PD-L1表达。
