Advancements in Composite Drug Delivery Systems for Osteosarcoma Treatment: Targeting ROS, Cuproptosis, and Mitochondrial Dysfunction

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and remains difficult to treat when metastatic, recurrent, or chemotherapy-resistant. Rather than viewing reactive oxygen species (ROS), mitochondrial dysfunction, and cuproptosis as independent therapeutic topics, this review integrates them into a single mechanism-to-material framework for osteosarcoma treatment. Mitochondria are a major source and target of ROS and also determine susceptibility to cuproptosis through mitochondrial respiration and protein lipoylation. Mechanistically, excess intracellular copper can directly bind lipoylated tricarboxylic-acid-cycle proteins, particularly dihydrolipoamide S-acetyltransferase, promoting protein aggregation, loss of iron–sulfur-cluster proteins, proteotoxic stress, and cell death. Composite drug delivery systems may exploit this vulnerability by increasing tumor-selective ROS, depleting antioxidant defenses, delivering copper or copper ionophores, targeting mitochondria, and responding to the osteosarcoma microenvironment. Importantly, copper-containing nanoplatforms should not automatically be classified as cuproptosis-inducing systems, because copper may also trigger chemodynamic oxidative injury through mechanisms that do not satisfy current molecular criteria for cuproptosis. We therefore distinguish osteosarcoma-specific evidence from findings extrapolated from other cancers, critically compare major delivery platforms and experimental models, and discuss immunological effects, toxicity, pharmacokinetics, biodistribution, manufacturing, and regulatory barriers. This integrated perspective suggests that the most promising future systems will be those that verify mechanism-specific biomarkers, achieve spatially controlled mitochondrial/copper exposure, and demonstrate efficacy and safety in clinically relevant orthotopic and immunocompetent osteosarcoma models.