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 (UPR^mt) 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 UPR^mt 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.