Trimetallic nano trap-mediated glycolytic and mitochondrial metabolism co-inhibition: ATP suppression for enhanced metal ion-interference therapy

Abstract

Mitochondria serve as central regulators of tumorigenesis, progression, metastasis, and chemoresistance, playing a pivotal role in cancer bioenergetics and thus representing prime targets for anticancer therapy. However, conventional strategies aimed at disrupting mitochondrial energy supply often exhibit limited efficacy due to the compensatory interplay between mitochondrial tricarboxylic acid cycle (TCA) and glycolysis. Herein, we developed a trimetallic nano-trap capable of achieving synergistic ATP depletion via dual-pathway metabolic interference. Specifically, this engineered system co-delivers Cu-MOF and CaO2 to trigger irreversible Cu2+/Ca2+ dual-overload, resulting in structural damage and functional impairment of mitochondria, thereby suppressing ATP generation. Concurrently, glucose is progressively depleted through the catalytic activity of Au NPs, effectively interrupting the glycolytic energy supply. By concomitantly inhibiting glycolysis and mitochondrial metabolism, this system achieves a marked reduction in ATP production. This ion interference-based strategy offers a promising paradigm to overcome metabolic plasticity in cancer treatment.