An injectable hydrogel with photothermal and chemodynamic therapies for targeted promotion of ferroptosis in oral squamous cell carcinoma

Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by increasing hydrogen peroxide (H₂O₂) concentrations or decreasing glutathione (GSH) levels. However, the intracellular antioxidative defense mechanisms endow the oral squamous cell carcinoma (OSCC) cells with ferroptosis resistance capacity. Therefore, injectable self-healing carboxymethyl chitosan (CMCS)/aldehyde-based hyaluronic acid (HA-CHO)/PVP-CuO₂ (PCu)/polydopamine (PDA) (CHPP) hydrogels were developed to promote ferroptosis through increasing H₂O₂ concentrations and decreasing GSH levels. The introduction of HA-CHO can directly target the CD44 receptor and form Schiff bonds <i>via</i> CMCS to build the backbone of CHPP hydrogels. The CHPP hydrogels can responsively release H₂O₂ to catalyze the production of hydroxyl radical (˙OH) <i>via</i> chemodynamic therapy (CDT) in the tumor microenvironment (TME), sustained depletion of GSH through the dual action of Cu²⁺ and ˙OH, and generate repeated high temperatures under photothermal therapy (PTT) for a direct OSCC-killing effect after the loading of PCu and PDA. In addition, the OSCC tissue RNA sequencing suggests that the differentially expressed genes of the CHPP hydrogels exerting the targeted OSCC therapy enrich the ferroptosis signaling pathways significantly. Then, liproxstatin-1 (a ferroptosis inhibitor) was utilized to recover the activation of glutathione peroxidase 4 (GPX4), which can weaken the therapeutic effect of CHPP on OSCC. The CHPP hydrogels are a promising strategy for the treatment of OSCC.