The composites of triple-helix glucan nanotubes/selenium nanoparticles target hepatocellular carcinoma to enhance ferroptosis by depleting glutathione and augmenting redox imbalance

• The nanocomposites directly reacted with GSH and H 2 O 2 to elevate oxidative stress. • The nanocomposites disturbed multiple metabolic pathways related to oxidative stress. • The nanocomposites could kill cancer by inducing cell apoptosis and ferroptosis. • The nanocomposites suppressed glutathione and thioredoxin antioxidant systems. Exacerbating oxidative stress has become a promising strategy for effective cancer therapy. However, the hyperactive antioxidant systems in tumor cells neutralize this effect, reducing potency and promoting drug resistance. Herein, we put forward a new insight into the cancer therapy by depleting glutathione (GSH) and inducing cellular redox imbalance based on selenium nanoparticles (SeNPs)-loaded β-glucan nanotube (BFP-Se) composed of natural triple-helix glucans, derived from black fungus. BFP-Se targeted tumor tissues through enhanced permeability and retention effects, enhancing the bioavailability of SeNPs. Metabolomics unveiled that BFP-Se related metabolic responses were mainly associated with oxidative stress in hepatoma cells. In vivo and in vitro experiments prove that BFP-Se effectively depleted the intracellular GSH, inhibited TXNIP/TRX and NRF2/GPX4-associated antioxidant systems expressions, while produced reactive oxygen species by reacting with intracellular H 2 O 2 , ultimately leading to apoptosis and ferroptosis of hepatoma cells. This work offers a deeper understanding of nanomedicine-bio interactions and provides a forward look at cancer therapy by depleting GSH and inducing cellular redox imbalance.