Cell-Anchored Lead-Free Piezoelectric KNN NPs Resisting Washout for Low-Intensity Ultrasound Driven Neuromodulation

Piezoelectric nanomaterials for wireless neuromodulation is a promising alternative to traditional electrical stimulation. However, the low-avidity between piezoelectric nanomaterials and cellular membranes leads to low efficiency of electrical signal transmission, which requires high-intensity thresholds of ultrasound stimulation (US). Here, lead-free piezoelectric (K,Na)NbO (KNN) nanoparticles (NPs) with cholesterol coating (KNNC) are presented, in which Cholesterol can be accommodated in the membrane and make them append on the plasma membrane. Compared to non-modified nanoparticles, cell-anchored KNNC NPs highly resist convective washout owing to high affinity of cholesterol to biological membranes, which enables highly efficient wireless electrical stimulation to activate cell impulses under low-intensity ultrasound. Meanwhile, after perfusion washing, the KNNC NPs distributed around the cells are washed away, while part of KNNC NPs remain on the surface of cell membrane still can induce significant Ca influx under US, similar to the group without washing, indicating the KNNC NPs appended on the cell play a major role in wireless electrical stimulation. Furthermore, the highly efficient electrical transmission of KNNC enables neural differentiation of stem cells in regulating synaptic plasticity by modulating Ca influx, demonstrating that KNNC NPs offer a perspective toward minimally invasive wireless neuromodulation therapies for neurological diseases.