Tailored theranostic nanoparticles cause efficient ferroptosis in head and neck squamous cell carcinoma through a reactive oxygen species “butterfly effect”

Multidrug resistance (MDR) is the main reason of chemotherapy failure in head and neck squamous cell carcinoma (HNSCC) patients, leading to the worst outcome. Recently, ferroptosis shows great potential in cancer therapy via abnormal intracellular ROS accumulation, which may bypass the MDR effect of HNSCC. Herein, SNP and DHA, which is a ferroptosis inducer, were loaded to nanoparticles of zeolite imidazolate framework (Zif-8) with surface-immobilized FA to achieve a synergist effect and target FR-overexpressing HNSCC cells through ferroptosis. As the donor of Fe2+ and nitric oxide (NO), SNP triggers DHA-Fe2+ reaction on one hand and NO correlative tumor inhibition on the other, which leads to intracellular formation of ROS. Loading capacity of the nanoparticles (NPs) reached 45.7% (DHA) and 13.8% (SNP) respectively. Once internalized, the pH-sensitive Zif-8 degraded in lysosomes and the drugs were released. In vitro study showed that the intracellular ROS level of cancer cell was greatly enhanced. Meanwhile, the cell viability decreased sharply to 15%. Apart from extra ROS formation, key antioxidants, including glutathione (GSH) and glutathione peroxidase 4 (GPX4), were also found inhibited. In vivo experiments demonstrated that the tumor inhibition rate of DHA/SNP@Zif-8-FA reached 66.93%. On the other hand, indocyanine green (ICG) was loaded in our nanoreactor so that the tumor could be tracked and visualized by both fluorescent and photoacoustic instruments. Above all, these remarkable features of ICG loaded DHA/SNP@Zif-8-FA (DHA/SNP/ICG@Zif-8-FA) may help in the development of more diagnostic and therapeutic treatments for HNSCC.