Yu Pei, Han Yubao, Meng Lulu, Tian Yanyuan, Jin Zhiwei, Luo Jun, Han Chao, Xu Wenjun, Kong Lingyi, Zhang Chao
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Acta Pharm Sin B. 2024 May;14(5):2039-2056. doi: 10.1016/j.apsb.2024.01.016. Epub 2024 Jan 27.
Osteosarcoma, a prevalent primary malignant bone tumor, often presents with lung metastases, severely impacting patient survival rates. Extracellular vesicles, particularly exosomes, play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions. However, the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure, with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown. This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site. This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate (MARCKS) expression. Addressing this phenomenon, in this study we employ cationic bovine serum albumin (CBSA) to form nanoparticles (CBSA-anta-194/215) electrostatic interaction with antagomir-miR-194/215. These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles (anta-194/215@Exo) targeting osteosarcoma lung metastatic sites. Intervention with bioengineered exosome mimetics (anta-194/215@Exo) not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice. These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS, making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.
骨肉瘤是一种常见的原发性恶性骨肿瘤，常伴有肺转移，严重影响患者生存率。细胞外囊泡，尤其是外泌体，在骨肉瘤相关肺部病变的形成和进展中起关键作用。然而，原发性骨肉瘤与外泌体介导的肺部病变之间的联系仍不清楚，肺转移灶对骨肉瘤进展的潜在影响也 largely 未知。本研究揭示了一种创新机制，即源自骨肉瘤肺转移部位的外泌体将 miR-194/215 簇转运至原发肿瘤部位。这种转运通过下调肉豆蔻酰化富含丙氨酸的 C 激酶底物（MARCKS）的表达来增强肺转移能力。针对这一现象，在本研究中我们使用阳离子牛血清白蛋白（CBSA）与抗 miR-194/215 形成纳米颗粒（CBSA-anta-194/215）静电相互作用。这些纳米颗粒被装载到靶向骨肉瘤肺转移部位的核酸耗尽的外泌体膜囊泡（anta-194/215@Exo）中。用生物工程外泌体模拟物（anta-194/215@Exo）进行干预不仅阻碍骨肉瘤进展，还显著延长荷瘤小鼠的寿命。这些发现表明，肺转移灶来源的外泌体通过转移靶向 MARCKS 的 miR-194/215 簇引发原发性骨肉瘤肺转移，使 miR-194/215 簇成为抑制骨肉瘤肺转移患者进展的有前景的治疗靶点。
