Self-Assembled Drug Nanocomplexes Reverses Tumor Thermoresistance and Depletes GSH to Optimize Mild Photothermal Therapy for Osteosarcoma

Osteosarcoma, a highly aggressive malignant bone tumor, presents significant treatment challenges. Photothermal therapy (PTT) is a promising therapeutic approach for OS; however, its efficacy is limited by dual resistance mechanisms: overexpression of heat shock protein 70 (HSP70) in tumor cells, which activates thermal defense pathways, and glutathione-mediated scavenging of photothermal-derived reactive oxygen species (ROS). To address these limitations, we developed a multifunctional nanodrug (CAI) via noncovalent assembly of Cu2+, apoptozole, and indocyanine green (ICG). In this system, apoptozole suppresses HSP70 to attenuate thermal resistance, while Cu2+ depletes GSH to amplify oxidative damage. Apoptozole and Cu2+ synergistically enhance the photothermal tumor ablation effect of ICG under laser irradiation. The results demonstrate preferential tumor accumulation of CAI via the enhanced permeation and retention (EPR) effect. Following cellular internalization, the acidic tumor microenvironment triggers CAI dissociation, releasing Cu2+ and apoptozole to synergistically sensitize OS cells to concurrent thermal and oxidative damage. This dual-action mechanism enhances mild PTT efficacy against OS while maintaining favorable biocompatibility. Transcriptomic profiling further revealed CAI-mediated modulation of immune response pathways, inflammatory chemotaxis, and ferroptosis-related signaling, suggesting potential for multimodal OS therapy. Our study proposes a rationally designed strategy to circumvent HSP70 and glutathione-mediated resistance in PTT and broadens the therapeutic arsenal for OS.