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) via 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，通常伴有肺转移，严重影响患者的生存率。细胞外囊泡，特别是外泌体，在骨肉瘤相关肺部病变的形成和进展中发挥着关键作用。然而，原发性骨肉瘤和外泌体介导的肺部病变之间的联系仍然不清楚，肺转移灶对骨肉瘤进展的潜在影响很大程度上未知。这项研究揭示了一种创新机制，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) 表达来增强肺转移能力。针对这一现象，在本研究中，我们采用阳离子牛血清白蛋白（CBSA）通过与 antagomir-miR-194/215 的静电相互作用形成纳米颗粒（CBSA-anta-194/215） 。这些纳米颗粒被加载到针对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。使用生物工程外泌体模拟物（anta-194/215@Exo）进行干预不仅可以阻止骨肉瘤的进展，还可以显着延长荷瘤小鼠的寿命。这些发现表明，肺转移灶衍生的外泌体通过转移靶向MARCKS的miR-194/215簇来启动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。