Precision Cuproptosis Activation via HER2‐Targeted Bimetallic MOF Nanoreactors Breaks Metabolic Adaptation in Aggressive Breast Cancers

Abstract Tumor heterogeneity and the single‐pathway inhibition mechanisms of trastuzumab represent major contributors to treatment failure in human epidermal growth factor receptor 2‐positive (HER2+) breast cancer. Cuproptosis, a promising copper‐dependent cell death mechanism, remains clinically constrained by its inherent reliance on copper bioavailability and tumor metabolic heterogeneity. Building upon these insights, this work developed an Elesclomol (ES)‐loaded delivery system employing copper‐based metal–organic frameworks (Cu MOFs) as carriers. This innovation effectively addresses rapid drug metabolism while enabling tumor microenvironment‐responsive controlled release. To enhance targeting capability and biocompatibility, the MOF is further coated with trastuzumab for HER2+ tumor‐specific delivery. This targeted biomimetic delivery system exhibits several critical features: 1) Active targeting of HER2‐overexpressing breast cancer cells; 2) Establishment of self‐amplifying copper accumulation through ES‐mediated efflux‐rebinding dynamics, decoupling therapeutic efficacy from endogenous copper levels; 3) Glutathione‐mediated Cu 2+ →Cu + conversion driving Fenton reactions that generate hydroxyl radicals to disrupt redox homeostasis; 4) Cu + binding to lipoylated tricarboxylic acid (TCA) cycle proteins, inducing mitochondrial proteotoxicity via iron‐sulfur cluster destabilization. In HER2+ breast cancer models, Zr‒Cu MOF@ES@aH (ZCEH) demonstrated 67% suppression of primary tumor growth with concurrent inhibition of lung metastasis. Collectively, this study enhances therapeutic drug sensitivity through material‐mediated cuproptosis, providing a strategic blueprint for advancing next‐generation cancer nanomedicine.