Ultrasound-activated piezoelectric nanoparticles suppress glycolysis for precision therapy of stress-associated breast cancer.

Abstract

Chronic stress has emerged as a critical factor that exacerbates cancer progression, yet its underlying mechanisms and targeted therapeutic strategies remain elusive. Herein, we demonstrate that restraint-induced stress significantly enhances breast tumor growth and proliferation in a murine model. To counteract this effect, we engineered a piezoelectric nanomaterial based on Cu/BaTiO₃ (CBTO) and show that ultrasound activation of CBTO (CBTO-US) effectively suppresses stress-driven tumor growth without adverse effects on body weight or food intake. At the molecular level, transcriptomic profiling (RNA-seq) revealed that restraint stress downregulates key pathways associated with apoptosis, MAPK signaling, and glycolysis, whereas CBTO-US treatment reverses these stress-induced transcriptional changes. Functional analyses demonstrated that CBTO-US markedly reduces lactate accumulation in both tumor tissues in vivo and in E0771 breast cancer cells in vitro under stress conditions. This reduction occurs independently of lactate dehydrogenase activity; consistent with this, Seahorse metabolic flux analysis confirmed that CBTO-US suppresses glycolytic activity upstream of lactate production. Mechanistically, CBTO-US increases the intracellular NAD⁺/NADH ratio and elevates cytosolic Ca²⁺ levels, leading to attenuation of stress- and lactate-induced ERK phosphorylation and consequent inhibition of MAPK signaling. Collectively, these results establish a piezoelectric-catalyzed metabolic regulation strategy that counteracts stress-driven tumor progression, highlighting CBTO-US as a potential therapeutic modality for stress-driven breast cancer. STATEMENT OF SIGNIFICANCE: Chronic stress facilitates breast cancer progression, but effective therapies targeting this link are lacking. Here, we show that ultrasound-activated piezoelectric nanoparticles (Cu/BaTiO₃) suppress stress-driven tumor growth by reprogramming cancer metabolism. These nanoparticles generate electrical signals under ultrasound, reducing lactate production and restoring cellular redox and calcium balance to block pro-cancer MAPK signaling. This work introduces a wireless, non-invasive strategy that converts mechanical energy into anti-cancer metabolic control-offering a new paradigm for treating stress-associated malignancies and broadening the therapeutic potential of piezoelectric nanomaterials.