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By co-delivering chemotherapeutic agents that induce ICD with immunomodulators that reprogram the TME, these platforms can achieve synergistic antitumor effects that are not attainable with either modality alone ( The mechanotherapeutic agent ketotifen has been shown to reprogram the TME by reducing tumor stiffness and increasing perfusion, thereby enhancing the delivery and efficacy of nanomedicine-based chemo-immunotherapy ( Nanocarrier-based epirubicin micelles (NC-6300) have demonstrated anti-tumor activity in sarcoma patients, and their combination with anti-PD-L1 antibody has been extensively studied in preclinical models ( 4.5 Overcoming drug resistance through nanocarrier-mediated gene therapy Non-coding RNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play critical roles in the development of chemoresistance in osteosarcoma, and their modulation using nanoparticle delivery systems represents a novel therapeutic approach ( Nanoparticle-based delivery of tumor-suppressive miRNAs has shown promise in overcoming drug resistance in osteosarcoma ( 4.6 Overcoming translational barriers: In Vivo stability and manufacturing hurdles Despite the immense preclinical promise of nanomedicine in osteosarcoma, several significant translational barriers must be addressed before clinical implementation ( Table 1