High‐Cubic Bornite Nanoparticle‐Enabled Photothermoelectric Catalysis Induces Dual Cuproptosis and Ferroptosis in Hepatocellular Carcinoma

ABSTRACT Optimizing the therapeutic efficacy of photothermoelectric catalysis (PTEC) remains challenging due to the intricate interdependencies among thermoelectric parameters. This study addresses the issue by developing high‐cubic bornite (Cu 5 FeS 4 , CFS) nanoparticles with phonon‐liquid electron‐crystal characteristics. During the heating/cooling processes, CFS nanoparticles could generate a self‐built‐in electric field to induce O 2 *− and 1 O 2 production via a cascaded photo‐thermal‐electric‐chemical energy conversion process. Meanwhile, bimetallic CFS nanoparticles enable heat‐promoted * OH generation and glutathione consumption to augment cellular oxidative stress. The CFS nanoparticles modified with anti‐glypican‐3 antibodies can effectively target hepatocellular carcinoma cells and induce cellular metabolic reprogramming. Exposed to the oxidative burden and metal ions, Huh7 cells exhibit mitochondrial protein aggregation, Fe–S cluster loss, and lipid peroxide accumulation, indicating the dual activation of cuproptosis and ferroptosis. In addition, the transcriptome analysis reveals the enrichment of cellular response to heat stress and reactive oxygen species, confirming the initiation of thermal and catalytic steps in the PTEC process. Consequently, this study provides a novel nanotherapeutic strategy for hepatocellular carcinoma and promotes the future design of PTEC‐based nanomedicines.