Multimodal graphene oxide nanoplatform integrating proteasome inhibition and phototherapy for synergistic oral cancer treatment

Multimodal therapeutic approaches hold the potential to revolutionize cancer treatment. Herein, we developed a chemo-photothermal-photodynamic therapeutic platform by loading a proteome inhibitor, BTZ, and photodynamic agent, IR820, into polydopamine-coated graphene oxide to form GO@PDA (BTZ, IR820) NPs. The developed NPs exhibit smaller particle size, homogeneous morphology, and laser-mediated drug release. The GO@PDA (BTZ, IR820) NPs exhibited an optimal photothermal conversion efficiency of 54.18%. GO@PDA (BTZ, IR820) NPs enhanced the uptake in the human hypopharyngeal squamous cell carcinoma (FaDU) spheroids and exhibited enhanced cytotoxicity (IC50: 18.53 ng/ml in the presence of laser). In vitro study in FaDU spheroid models also demonstrated mitochondrial dysfunction, reactive oxygen species (ROS) generation, and cell cycle arrest, leading to cancer cell death. The developed NPs also exhibited the BTZ-mediated expression of endoplasmic reticulum (ER) stress-related proteins, including CHOP, PERK, and BiP, leading to ER stress-mediated cell death in FaDU multicellular spheroids. The developed nanoplatform offers a synergistic multimodal therapeutic strategy and holds potential for tumor ablation in oral cancer.