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 H2O2 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 H2O2, 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.