Mesenchymal stem cell-derived exosomes (MSC-Exos) are a promising cell-free therapy for knee osteoarthritis (OA). OA is a degenerative disease characterized by progressive cartilage destruction, subchondral bone remodeling, and synovial inflammation. Current treatments focus on symptom relief but do not effectively slow disease progression. MSC-Exos, derived from mesenchymal stem cells, have shown potential in regenerative therapy and tissue engineering. Preclinical studies indicate that MSC-Exos can promote cartilage repair, reduce inflammation, and modulate immune responses. They achieve this by enhancing chondrocyte proliferation, inhibiting apoptosis, and regulating the extracellular matrix (ECM) balance. MSC-Exos also exhibit anti-inflammatory effects by modulating macrophage polarization and reducing pro-inflammatory cytokines. MSC-Exos can be engineered to improve therapeutic efficacy through various strategies, including cargo loading, surface modification, and changes in production environments. These modifications enhance targeting, stability, and therapeutic outcomes. For example, MSC-Exos can be loaded with miRNAs, lncRNAs, or small molecules to target specific pathways involved in OA progression. Surface modifications, such as attaching ligands or combining with biomaterials, improve the delivery and retention of exosomes at the disease site. Additionally, 3D culture methods and bioreactors have been used to increase exosome yield and purity. Despite their potential, challenges remain in the clinical application of MSC-Exos, including variability in preparation methods, the need for standardized production, and the risk of immune responses. However, ongoing clinical trials suggest that MSC-Exos are safe and effective for OA treatment. They offer a promising alternative to joint replacement surgery, with the potential to regenerate cartilage and improve joint function. Future research should focus on optimizing exosome production, enhancing targeting, and ensuring consistent therapeutic outcomes. MSC-Exos represent a significant advancement in cell-free therapy for OA, with the potential to revolutionize the treatment of this debilitating disease.Mesenchymal stem cell-derived exosomes (MSC-Exos) are a promising cell-free therapy for knee osteoarthritis (OA). OA is a degenerative disease characterized by progressive cartilage destruction, subchondral bone remodeling, and synovial inflammation. Current treatments focus on symptom relief but do not effectively slow disease progression. MSC-Exos, derived from mesenchymal stem cells, have shown potential in regenerative therapy and tissue engineering. Preclinical studies indicate that MSC-Exos can promote cartilage repair, reduce inflammation, and modulate immune responses. They achieve this by enhancing chondrocyte proliferation, inhibiting apoptosis, and regulating the extracellular matrix (ECM) balance. MSC-Exos also exhibit anti-inflammatory effects by modulating macrophage polarization and reducing pro-inflammatory cytokines. MSC-Exos can be engineered to improve therapeutic efficacy through various strategies, including cargo loading, surface modification, and changes in production environments. These modifications enhance targeting, stability, and therapeutic outcomes. For example, MSC-Exos can be loaded with miRNAs, lncRNAs, or small molecules to target specific pathways involved in OA progression. Surface modifications, such as attaching ligands or combining with biomaterials, improve the delivery and retention of exosomes at the disease site. Additionally, 3D culture methods and bioreactors have been used to increase exosome yield and purity. Despite their potential, challenges remain in the clinical application of MSC-Exos, including variability in preparation methods, the need for standardized production, and the risk of immune responses. However, ongoing clinical trials suggest that MSC-Exos are safe and effective for OA treatment. They offer a promising alternative to joint replacement surgery, with the potential to regenerate cartilage and improve joint function. Future research should focus on optimizing exosome production, enhancing targeting, and ensuring consistent therapeutic outcomes. MSC-Exos represent a significant advancement in cell-free therapy for OA, with the potential to revolutionize the treatment of this debilitating disease.