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

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 Fe³⁺ and Cu²⁺ react with GSH to form Fe²⁺ and Cu⁺, thereby damaging the antioxidant system. To promote ferroptosis, these ions react with H₂O₂ in Fenton/Fenton-like ways, producing harmful hydroxyl radicals (•OH). High-valent Fe³⁺ and Cu²⁺ are created in the meantime, creating a cycle that depletes GSH and generates •OH. When H₂O₂ 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.