Wireless Localized Electrical Stimulation Generated by an Ultrasound‐Driven Piezoelectric Discharge Regulates Proinflammatory Macrophage Polarization

Proinflammatory (M1) macrophages play a vital role in antitumor immunity, and regulation of proinflammatory macrophage polarization is critical for immunotherapy. The polarization of macrophages can be regulated by biological or chemical stimulation, but investigations of the regulatory effect of physical stimulation are limited. Herein, regulating macrophage polarization with localized electrical signals derived from a piezoelectric β-phase poly(vinylidene fluoride) (β-PVDF) film in a wireless mode is proposed. Charges released on the surface of the β-PVDF film driven by ultrasonic irradiation can significantly enhance the M1 polarization of macrophages. Mechanistic investigation confirms that electrical potentials rather than reactive oxygen species and mechanical forces enable Ca²⁺ influx through voltage-gated channels and establishment of the Ca²⁺-CAMK2A-NF-κB axis to promote the proinflammatory macrophage response during ultrasound treatment. Piezoelectric material-mediated electrical signal-activated proinflammatory macrophages significantly inhibit tumor cell proliferation. A method for electrogenetic regulation of immune cells as well as a powerful tool for engineering macrophages for immunotherapy is provided here.