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

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.