Osteosarcoma is a highly aggressive bone tumor that primarily affects children and adolescents. It is characterized by high rates of recurrence and metastasis, with the tumor microenvironment playing a pivotal role in disease progression. Exosomes, small extracellular vesicles secreted by various cell types, exert dual roles in osteosarcoma. On one hand, exosomes derived from osteosarcoma cells remodel the microenvironment to facilitate tumor progression. For instance, they carry miR-501-3p to activate the PTEN/PI3K/Akt signaling pathway, promoting osteoclastogenesis and bone destruction; TGF-β1/3 stimulates bone marrow-derived mesenchymal stem cells (BMSCs) to secrete IL-6 and IL-8, enhancing the inflammatory microenvironment; and miR-25-3p suppresses DKK3, thereby promoting angiogenesis and invasion. Moreover, exosomes contribute to the formation of a pre-metastatic niche by transporting miR-21 and miR-675, which promote lung metastasis, activate cancer-associated fibroblasts, and enhance invasiveness via the linc00881/miR-29c-3p/MMP2 axis. Conversely, exosomes derived from mesenchymal stem cells deliver tumor-suppressive miRNAs such as miR-1913, miR-150, and miR-206, which target NRSN2, IGF2BP1, and TRA2B, thereby inhibiting tumor growth. In the context of drug resistance, osteosarcoma-derived exosomes transport MDR-1 mRNA and circRNA_103801, contributing to chemotherapy resistance. Additionally, TGF-β-induced IL-6 activates the STAT3 pathway, further enhancing resistance. In terms of immune modulation, these exosomes suppress T cell and NK cell activity and upregulate PDL1 expression, promoting immune evasion. Exosomes also hold therapeutic potential. They can serve as drug delivery vehicles, for example, carrying doxorubicin or kanamycin, to achieve targeted cytotoxicity via ferroptosis or apoptosis. Engineered exosomes enriched with miR-101 or MEG3 have been shown to inhibit metastasis, while plant-derived exosome-like nanoparticles activate the P38/JNK pathway to induce apoptosis. These approaches aim to improve therapeutic efficacy while minimizing adverse effects. In summary, exosomes play multifaceted roles in the pathogenesis of osteosarcoma and offer promising avenues for early diagnosis, prognostic assessment, and precision therapy, including pathway-targeted strategies. However, challenges remain in optimizing exosome isolation, standardizing large-scale production, and validating clinical applications. Addressing these issues is essential for translating laboratory findings into effective clinical treatments.

Osteosarcoma is a highly aggressive bone tumor that primarily affects children and adolescents. It is characterized by high rates of recurrence and metastasis, with the tumor microenvironment playing a pivotal role in disease progression. Exosomes, small extracellular vesicles secreted by various cell types, exert dual roles in osteosarcoma. On one hand, exosomes derived from osteosarcoma cells remodel the microenvironment to facilitate tumor progression. For instance, they carry miR-501-3p to activate the PTEN/PI3K/Akt signaling pathway, promoting osteoclastogenesis and bone destruction; TGF-β1/3 stimulates bone marrow-derived mesenchymal stem cells (BMSCs) to secrete IL-6 and IL-8, enhancing the inflammatory microenvironment; and miR-25-3p suppresses DKK3, thereby promoting angiogenesis and invasion. Moreover, exosomes contribute to the formation of a pre-metastatic niche by transporting miR-21 and miR-675, which promote lung metastasis, activate cancer-associated fibroblasts, and enhance invasiveness via the linc00881/miR-29c-3p/MMP2 axis. Conversely, exosomes derived from mesenchymal stem cells deliver tumor-suppressive miRNAs such as miR-1913, miR-150, and miR-206, which target NRSN2, IGF2BP1, and TRA2B, thereby inhibiting tumor growth. In the context of drug resistance, osteosarcoma-derived exosomes transport MDR-1 mRNA and circRNA_103801, contributing to chemotherapy resistance. Additionally, TGF-β-induced IL-6 activates the STAT3 pathway, further enhancing resistance. In terms of immune modulation, these exosomes suppress T cell and NK cell activity and upregulate PDL1 expression, promoting immune evasion. Exosomes also hold therapeutic potential. They can serve as drug delivery vehicles, for example, carrying doxorubicin or kanamycin, to achieve targeted cytotoxicity via ferroptosis or apoptosis. Engineered exosomes enriched with miR-101 or MEG3 have been shown to inhibit metastasis, while plant-derived exosome-like nanoparticles activate the P38/JNK pathway to induce apoptosis. These approaches aim to improve therapeutic efficacy while minimizing adverse effects. In summary, exosomes play multifaceted roles in the pathogenesis of osteosarcoma and offer promising avenues for early diagnosis, prognostic assessment, and precision therapy, including pathway-targeted strategies. However, challenges remain in optimizing exosome isolation, standardizing large-scale production, and validating clinical applications. Addressing these issues is essential for translating laboratory findings into effective clinical treatments.