Self-reinforced nanoreactor for apoptosis/ferroptosis synergistic therapy of head and neck squamous cell carcinoma

Conventional treatments for head and neck squamous cell carcinoma (HNSCC) cause severe side effects and functional impairment. Chemodynamic therapy (CDT), a reactive oxidative stress (ROS)-based therapy, exploits H₂O₂ in the tumor micro-environment to produce large amounts of cytotoxic ROS to destroy cancer cells. Monotonic CDT efficacy is severely constrained by slow Fenton kinetics and insufficient intra-tumoral H₂O₂ content. In order to overcome these barriers, a multifunctional self-reinforced nanoreactor, MAGFH, was developed for the eradication of HNSCC. This nano-system employed an Fe-based metal-organic framework, MIL-100, to deliver artesunate (ART) for the exertion of H₂O₂-independent CDT. A gallic acid (GA)-Fe³⁺ metal-polyphenol network (MPN) coating was introduced to enhance the Fenton reaction by accelerating iron redox cycling while conferring photothermal therapy (PTT) effect. Hyaluronic acid (HA) was covered on the outermost layer to enable the tumor targeting. Following endocytosis into cancer cells, the released Fe³⁺ was reduced into Fe²⁺ by the consumption of glutathione (GSH), thereby catalyzing the production of hydroxyl radicals (OH) via the Fenton reaction. The GA-Fe network functioned as an amplifier for the iron redox cycle. Concurrently, the activation of ART by Fe²⁺ led to the generation of highly cytotoxic superoxide anions (O₂⁻) and C-centered free radicals (C). The near infrared laser (808 nm) irradiation synergistically enhanced ROS generation and GSH depletion, resulting in the high accumulation of ROS and the dysregulation of redox homeostasis, subsequently inducing cell apoptosis and ferroptosis. In addition, the introduction of the GA-Fe MPN conferred both photoacoustic imaging (PAI) and T₁ magnetic resonance imaging (MRI) capabilities, enabling the integration of therapeutics and diagnosis. Collectively, this work established a PAI/MRI-guided nanoplatform for self-amplifying CDT/PTT against HNSCC via dual induction of apoptosis-ferroptosis.