Bioinspired polymer-incorporated copper/iron nanozyme to boost cascade ROS accumulation for augmented hepatocellular carcinoma cuproptosis/ferroptosis.

Hepatocellular carcinoma (HCC), an infamously incurable tumor, is extremely sensitive to ferroptosis, and its development is greatly aided by the glutathione (GSH) antioxidant defense system. We present a gelatin (GT)/hyaluronic acid (HA)-stabilized Copper (Cu) and Iron (Fe) nanoparticle (5CFGH NPs) for HCC therapy that uses a self-amplified dual mechanism of cuproptosis and ferroptosis. It has a Cu/Fe mass ratio of 5:5. HA in 5CFGH selectively binds to HCC cells overexpressing CD44 receptor. This enables 5CFGH to release metal ions in acidic conditions after entering cells through receptor-mediated endocytosis. In the HepG2 cell line, released Fe and Cu react with GSH to form Fe and Cu, thereby damaging the antioxidant system. To promote ferroptosis, these ions react with HO in Fenton/Fenton-like ways, producing harmful hydroxyl radicals (•OH). High-valent Fe and Cu are created in the meantime, creating a cycle that depletes GSH and generates •OH. When HO is depleted, the cells' increased Cu level leads to the aggregation of lipoylated proteins, which intensifies cuproptosis. 5CFGH showed excellent cell-killing efficiency against HCC. Overall, 5CFGH is a possible drug that could induce self-amplification of cuproptosis/ferroptosis in HCC.