Wireless discharge of piezoelectric nanogenerator opens voltage-gated ion channels for calcium overload-mediated tumor treatment

Abstract

Calcium overload-mediated tumor treatment conventionally necessitates calcium-containing drugs. However, these drugs are susceptible to calcium ion leakage during in vivo delivery, potentially causing adverse effects such as hypercalcemia and hypertension. Furthermore, voltage-gated ion channels (VGICs) on the tumor cell membrane stringently regulate calcium ion influx to preserve intracellular calcium homeostasis. To address these issues, a calcium-free piezoelectric nanogenerator, (K, Na) NbO₃ (KNN), capable of local and wireless discharge (at a voltage of up to 0.4 mV) into tumors under ultrasound (US) excitation, is designed to open VGICs. Given the significantly higher extracellular calcium ion concentration compared to intracellular levels (approximately 15,000-fold), a substantial influx of calcium ions ensures, leading to intracellular calcium overload. Concurrently, US stimulates KNN to undergo piezoelectric catalysis, converting water into reactive oxygen species (ROS). The synergistic effect of calcium overload and high ROS oxidation induces mitochondrial damage, culminating in tumor elimination. Additionally, the calcium ion influx induces polarization of tumor-associated macrophages from an immunosuppressive M2 phenotype to an immunity-promoting M1 phenotype, thereby enhancing systemic anti-tumor immune responses. This study demonstrates that local electric field within tumors can open VGICs for efficient and safe calcium overload-mediated tumor treatment, showing great potential for clinical translation.