Liposome-mediated delivery of a ruthenium-based metallodrug to overcome cisplatin resistance in osteosarcoma.

The treatment of osteosarcoma has remained largely unchanged over the past decades. Its low incidence, predominantly affecting children and young adults, combined with marked biological heterogeneity, poses major challenges to the development of effective therapies, and currently approved regimens often yield variable responses. Additionally, the frequent emergence of drug-resistant phenotypes in these mesenchymal tumors further compromises treatment success. As a result, despite substantial research efforts, patients with osteosarcoma still face a poor prognosis, underscoring the urgent need for improved therapeutic strategies. Alongside doxorubicin and methotrexate, cisplatin is one of the primary first-line chemotherapeutic agents used for osteosarcoma. However, like other cytotoxic drugs, cisplatin is limited by severe systemic toxicity and the development of resistance. In this study, we investigated the antitumor potential of a novel ruthenium organometallic compound, Ru3, and its liposomal encapsulation as a nanomedicine approach to provide a safer and more effective alternative to platinum-based therapy for both cisplatin-resistant and parental osteosarcoma models. In vitro, both free and liposomal Ru3 displayed stronger cytotoxicity than cisplatin in most models, effectively reversing drug resistance. Ru3 formulations also maintained potent activity in 3D osteosarcoma spheroids and selectively targeted cancer stem cell-enriched tumorspheres. In vivo, treatment with liposomal Ru3 in mice bearing cisplatin-resistant xenografts produced superior therapeutic outcomes and was better tolerated than cisplatin, alleviating its systemic toxicity. Overall, these findings support ruthenium-based metallodrugs delivered via liposomes as promising alternatives to platinum-based chemotherapy for osteosarcoma management.