High‐Index Facet‐Distorted Lanthanum Cuprate for Ultrasound‐Triggered Cuproptosis and Cascade‐Amplified Antitumor Therapy

ABSTRACT Triple‐negative breast cancer (TNBC) poses a severe clinical challenge due to high recurrence, metastasis, and chemoresistance. To address this, high‐index facet (1 1 3) ‐distorted lanthanum cuprate (LCO) nanosheets are established. Ultrasound (US) activated LCO and amplified tumor suppression via the “metabolism‐inflammation‐immunity” cascade by synergistically activating cuproptosis/ions overload/pyroptosis and immunogenic cell death (ICD). Specifically, US activation of LCO efficiently generates reactive oxygen species (ROS) and reduces glutathione (GSH) levels, reversing the antioxidant tumor microenvironment. Enhanced Cu ²⁺ /Cu ⁺ conversion under US triggers cuproptosis, and La ³⁺ released from LCO acted as super calcium, enhancing mitochondrial Ca ²⁺ uptake and thereby inducing ions overload. These processes synergistically damage mitochondria, driving ROS accumulation and activating the NLRP3 inflammasome, ultimately triggering pyroptosis. This strategy achieves potent tumor cell killing and a remarkable 92.4% tumor inhibition rate. Collectively, LCO‐induced synergistic cuproptosis/ions overload/pyroptosis activates robust antitumor immunity, offering a unique and promising paradigm for efficient TNBC therapy.