Acoustoelectric nanoregulator for modulating the endoplasmic reticulum and mitochondria in cell fate regulation

The endoplasmic reticulum (ER) and mitochondria are critical organelles in maintaining cellular homeostasis and regulating cell fate. However, current biological and chemical approaches for modulating ER and mitochondrial functions often lack specificity and spatiotemporal controllability, potentially leading to off-target or systemic effects that limit their clinical applications. Here, by synthesizing a physical stimulus-based acoustoelectric nanoregulator, barium zirconate titanate (BZT) nanoparticles (NPs) with enhanced piezoelectric properties, we aimed to modulate ER and mitochondrial functions by regulating intracellular concentrations of calcium ions (Ca²⁺) and hydrogen ions (H⁺), thereby enabling spatiotemporally controllable modulation of cell fate. BZT NPs significantly modulated calcium ion dynamics and pH in tumor cells under ultrasound stimulation, accompanied by perturbations in ER and mitochondrial homeostasis, induction of ER stress and mitophagy, and ultimately alterations in cell fate. In the tumor-bearing mouse model, the acoustoelectric nanoregulator spatiotemporally modulates the intracellular environment through electrical signaling and ionic dynamic modulation under ultrasound stimulation, expanding the application prospects of physical stimulation-based strategies for abnormal cell function regulation. Our findings provide fresh perspectives for understanding cellular stress responses and cell fate determination processes, and lay the foundation for developing novel interventions in precision therapy and cell engineering applications.