A Stimulus‐Responsive Ternary Heterojunction Boosting Oxidative Stress, Cuproptosis for Melanoma Therapy

Abstract Cuproptosis, a recently discovered copper‐dependent cell death, presents significant potential for the development of copper‐based nanoparticles to induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction, denoted as HACT, composed of core–shell Au@Cu 2 O nanocubes with surface‐deposited Titanium Dioxide quantum dots and modified with hyaluronic acid is introduced. Compared to core–shell AC NCs, the TiO 2 /Au@Cu 2 O exhibits improved energy structure optimization, successfully separating electron‐hole pairs for redox use. This optimization results in a more rapid generation of singlet oxygen and hydroxyl radicals triggering oxidative stress under ultrasound radiation. Furthermore, the HACT NCs initiate cuproptosis by Fenton‐like reaction and acidic environment, leading to the sequential release of cupric and cuprous ions. This accumulation of copper induces the aggregation of lipoylated proteins and reduces iron‐sulfur proteins, ultimately initiating cuproptosis. More importantly, HACT NCs show a tendency to selectively target cancer cells, thereby granting them a degree of biosecurity. This report introduces a ternary heterojunction capable of triggering both cuproptosis and oxidative stress‐related combination therapy in a stimulus‐responsive manner. It can energize efforts to develop effective melanoma treatment strategies using Cu‐based nanoparticles through rational design.