Self-propelled double-silicon-shell-coated Janus nanomotors integrating PTT/CDT/GT therapy to enhance synergistic ferroptosis in cancer therapy.

The effective induction of ferroptosis represents a novel strategy for cancer treatment. This study developed a near-infrared (NIR)-responsive Janus nanomotor (CP@SiO2@RSiO2&PMO@SNP) that synergistically amplifies ferroptosis through dual glutathione (GSH) depletion. The nanomotor comprises a rough silica head incorporating copper-doped Prussian blue (CP) and a mesoporous organosilica tail loaded with sodium nitroprusside (SNP). Under 808 nm irradiation, the photothermal effects of the CP core induce a cascade reaction that enhances Cu2 +-catalyzed ·OH production, depletes GSH, and inhibits glutathione peroxidase 4 (GPX4). This process leads to the accumulation of lethal lipid peroxidation (LPO) and activates ferroptosis. The concurrently released nitric oxide (NO) not only promotes deep tumor penetration but also depletes residual GSH. This process amplifies the initial GSH depletion mediated by Cu2+, thereby augmenting ferroptosis and ultimately disrupting cellular redox homeostasis. By integrating photothermal therapy (PTT), chemodynamic therapy (CDT) and gas therapy (GT), this innovative design synergistically disrupts intracellular redox homeostasis, enabling GPX4 inactivation alongside reactive oxygen species (ROS) accumulation to ultimately trigger efficient ferroptosis and apoptosis in tumor cells. This synergistic multi-modal approach underscores the platform's distinct advantages for ferroptosis-mediated cancer therapy.