Glutathione-responsive gambogic acid-conjugated carboxymethyl chitosan/graphene quantum dot nanoparticles for chemo-photothermal-photodynamic synergistic therapy of drug-resistant breast cancer

Aims Breast cancer (BC) remains the most prevalent malignancy in women, with conventional chemotherapy limited by drug resistance. This study develops a glutathione (GSH)-responsive nanoplatform combining chemotherapy with phototherapy against drug-resistant BC.Methods Gambogic acid (GA) was conjugated to carboxymethyl chitosan via disulfide bonds (GA-SS-CMCS, GSC), then loaded with graphene quantum dots (GQDs) to form GSC@GQD nanocomposites. The formulation was characterized by TEM, DLS, and NMR; photothermal performance, drug release, ROS generation, hemocompatibility, and anti-tumor efficacy were evaluated in MCF-7, MCF-7/ADR cells and MCF-7/ADR xenografts.Results GSC@GQD showed uniform morphology (~180 nm), GSH-triggered GA release (94% at 48 h), and hemolysis <5%. Under 808 nm irradiation, GSC@GQD raised temperature by 20 °C (vs. 9 °C for free GQDs), induced intracellular ROS accumulation, and achieved apoptosis rates of 86% (MCF-7) and 76% (MCF-7/ADR). In vivo, GSC@GQD + NIR suppressed tumor growth with satisfactory biosafety.Conclusions GSC@GQD integrates chemotherapy, photodynamic and photothermal therapy into a GSH-responsive platform, offering a promising strategy against drug-resistant BC.