Human Serum Albumin Mediated Controllable Synthesis of Defect‐Rich Copper Hydroxide Nanowire for Cuproptosis‐Based Anti‐Tumor Therapy

Abstract Cuproptosis, as a newly identified form of programmed cell death, shows great promise in cancer treatment. Efficient Cu + delivery while avoiding systemic toxicity and elimination of the resistance from over‐expressed intracellular copper chelator glutathione (GSH) are critical for cuproptosis. Herein, this work innovatively constructs a biocompatible and defect‐rich copper hydroxide nanowire (HCu nanowire) through a human serum albumin (HSA) mediated biomineralization method. This work finds that the morphology and size of HCu nanowires can be controlled adjusted by the feed ratio of HSA and Cu 2+ . Remarkably, except for outstanding biocompatibility, HSA coordination endows HCu nanowires abundant oxygen vacancies (OVs), and the defect‐rich HCu nanowire possesses excellent GSH consumption efficiency. Density functional theory studies indicate that OVs change GSH absorption energy on defective HCu nanowires. In cancer cells, HCu nanowires deplete GSH and simultaneously produce sufficient free Cu + for enhanced cuproptosis. Meanwhile, Cu + can catalyze endogenous H 2 O 2 into hydroxyl radicals (·OH) via a Fenton‐like reaction. Thus, synergetic cuproptosis and ROS mediated apoptosis against tumor are achieved. The experimental results show that HCu nanowires have a better performance in both antitumor efficiency and safety compared with chemotherapeutic drug Dox at the same dose, demonstrating its great potential in clinical applications.