Pathological angiogenesis frequently occurs in
tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating
tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless
electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve
tumor vascular normalization. Polarized
barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular
calcium ion gradient by wireless electrical stimulation. In vivo
tumor-bearing mouse model indicated that wireless electrical stimulation normalized
tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-
tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug
doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant
tumors.