Chondrosarcomas (CHS) constitute approximately 20% of all primary malignant bone tumors, characterized by a slow growth rate with initial manifestation of few signs and symptoms. These malignant cartilaginous neoplasms, particularly those with dedifferentiated histological subtypes, pose significant therapeutic challenges, as they exhibit high resistance to both radiation and chemotherapy. Ranging from relatively benign, low-grade tumors (grade I) to aggressive high-grade tumors with the potential for lung metastases and a grim prognosis, there is a critical need for innovative diagnostic and therapeutic approaches, particularly for patients with more aggressive forms. Herein, small extracellular vesicles (sEVs) derived from mesenchymal stem cells are presented as an efficient nanodelivery tool to enhance drug penetration in an in vitro 3D model of CHS. Employing high-pressure homogenization (HPH), we achieved unprecedented encapsulation efficiency of doxorubicin (DXR) in sEVs derived from mesenchymal stem cells (MSC-EVs). Subsequently, a comparative analysis between free DXR and MSC-EVs encapsulated with DXR (DXR-MSC-EVs) was conducted to assess their penetration and uptake efficacy in the 3D model. The results unveiled a higher incidence of necrotic cells and a more pronounced toxic effect with DXR-MSC-EVs compared to DXR alone. This underscores the remarkable ability of MSC-EVs to deliver drugs in complex environments, highlighting their potential application in the treatment of aggressive CHS.