In vivo Testing of Nanotherapeutics for Osteosarcoma Treatment: Translational Challenges and Solutions.

Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and teenagers, characterized by aggressiveness and early metastasis especially to the lungs. OS management is complex and combined-modality therapy involving surgery, chemotherapy and immunotherapy is common. The standard care treatment utilizing doxorubicin, cisplatin, and high-dose methotrexate is a combination ("MAP") not changed in more than 40 years that often confronts incomplete tumor removal, recurrence, drug resistance, and severe side effects. Recent advancements in nano- and precision medicine have introduced tumor-targeted drug delivery strategies through multifunctional nanocarriers which aim to enhance therapeutic efficacy by preventing rapid clearance, prolonging circulation time and improving accumulation at tumor sites while minimizing adverse effects. Although many of these smart Nanotherapeutics are still at the preclinical stage, their unique properties make their promotion in OS clinical applications a challenge. Starting from an overview of the current approved OS therapies, this review reports a systematic analysis of in vivo studies published in the last decade that employ multifunctional nanosystems, drug delivery strategies and cutting-edge technologies in chemo-, immuno- and gene therapy for OS management providing an overview of the potential and challenges of these innovative treatment strategies. Our comprehensive literature analysis points out their certain antitumoral effects in OS preclinical models; however, overcoming translational bottlenecks remains a critical challenge, as promising preclinical findings often fail to translate into effective clinical therapies. Moreover, extended long-term observation in clinical studies is still required together with an in-depth understanding of the unique genetics and biology of OS, given the complex heterogeneity of the tumor microenvironment. By analyzing the limitations of conventional therapies, the latest advancements in nanotechnology alongside key bottlenecks in clinical translation of nanotherapeutics for OS, this review provides valuable insight into future directions, particularly for combination regimens, fostering progress in OS clinical research and supporting the development of innovative and personalized therapies.