Precision targeting of CuET overload to disrupt mitochondrial unfolded protein response by integrated liposome

Mitochondria in breast cancer play a critical role in survival and adaptation to dynamic environments. Thus, targeting mitochondria emerges as a promising therapeutic strategy for breast cancer. However, the adaptive unfolded protein response in mitochondria (UPRmt) due to mitochondrial unspecific distribution might contribute to diminished therapeutic outcomes. Herein, mitochondrial targeting liposome agents (CTPP-Lipid) are constructed and adopted for delivering the copper ion (CuET-DSF), which is especially sensitive for mitochondria-abundant breast tumors. In brief, the CTPP-Lipid@CuET achieves the goal of Cu2+ overloading by mitochondria targeting delivery. This rapidly increases ROS production, disrupts mitochondrial structure, and avoids the adaptive UPRmt formation, finally leading to apoptosis of breast cancer cells. In general, the Cu2+ overloading at mitochondria by CTPP-Lipid@CuET is a potential strategy for antitumor therapy, providing new insights into breast tumor therapy.