RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC.
RNA干扰是一种强大的基因沉默工具，具有潜在的临床应用价值。然而，由于缺乏合适的载体，其治疗应用面临挑战。外泌体是稳定的小型内源性囊泡，能够将功能性分子转运至靶细胞，使其成为理想的小干扰RNA（siRNA）载体。本研究阐明了患者来源的外泌体作为siRNA载体在卵巢癌治疗中的潜力。外泌体提取自卵巢癌患者手术中采集的大网膜原代成纤维细胞培养基。研究选择MET原癌基因受体酪氨酸激酶（MET）作为基因沉默靶点，合成c-Met siRNA并通过电穿孔技术将其载入外泌体（Met-siExosomes），随后在体外和体内评估了Met-siExosomes的治疗效果。实验结果显示，Met-siExosomes能下调c-Met蛋白水平，抑制卵巢癌细胞的增殖、迁移和侵袭能力。在使用SKOV3-13和ES-2细胞进行的异种移植实验中，Met-siExosomes能够选择性富集于腹膜播散性肿瘤。腹腔给药治疗可抑制癌细胞中c-Met下游靶点表达，并显著延长小鼠生存期。本研究证实合成的siRNA能通过外泌体成功且选择性地递送至腹膜播散性肿瘤。鉴于卵巢癌患者常规接受大网膜切除术且易于从大网膜中获取大量成纤维细胞，患者来源的外泌体有望成为治疗卵巢癌的潜在siRNA递送载体。
Patient-Derived Exosomes as siRNA Carriers in Ovarian Cancer Treatment
肿瘤(癌症)患者之家