Nanoquadruplex-driven hydrogen therapy: NIR-controlled release for targeted cancer ferroptosis

Hydrogen therapy as an emerging strategy for anticancer medicine is attracting attention. However, the limitations of effective hydrogen storage and release have hindered its development and application for hydrogen therapy. Herein, a high hydrogen storage nanoquadruplex (PdH_0.2)₄Se based on a palladium-selenium core has been designed and shows enhanced intratumoral accumulation via an enhanced permeability and retention (EPR) effect. High-efficiency hydrogen can be released from (PdH_0.2)₄Se, activated by near infrared irradiation (NIR), and combines with available selenium (Se) to produce highly toxic hydrogen selenide (H₂Se), which in turn unbalances the GSH/GSSG ratio and induces ROS overproduction. The effect demonstrates that (PdH_0.2)₄Se irradiated by NIR significantly inhibits cancer cell proliferation, migration, invasion and angiogenesis in vitro. Furthermore, irradiation of (PdH_0.2)₄Se by NIR can induce significant ferroptosis of cancer cells by triggering mitochondrial dysfunction, ROS generation and lipid peroxidation-mediated oxidative damage in vitro. Finally, NIR irradiated (PdH_0.2)₄Se also exhibits tumor-targeted photothermal imaging, and inhibition of tumor growth in vivo activating cancer ferroptosis. Importantly, (PdH_0.2)₄Se demonstrates excellent safety and biocompatibility in vitro and in vivo. Thus together, our findings support the rational design of an effective hydrogen storage (PdH_0.2)₄Se nanoquadruplex with NIR-controlled release causing an unbalance of cellular GSH/GSSG and inducing cancer ferroptosis could be a highly efficient strategy for hydrogen-mediated cancer therapy.