Aggregation-Enhanced Piezoelectric Nanotransducers Facilitate Transgene-Free Wireless Neurostimulation under Low-Intensity Focused Ultrasound

Piezoelectric nanotransducers driven by low-intensity focused ultrasound offer a nongenetic and spatially addressable strategy for neuromodulation, but their weak piezoelectric outputs and uncontrolled cellular internalization may result in limited efficacy. Here, we propose an aggregation-enhanced piezoelectric nanotransducer constructed by assembling 10 nm BaTiO₃ piezoelectric nanoparticles onto porous UiO-66 metal-organic framework (MOF) cores and coating them with conductive polydopamine, which produces submicrometer structures with strengthened electric-field coupling and reduced cellular uptake. Under 1 MHz low-intensity focused ultrasound, these nanotransducers have been demonstrated to be able to evoke voltage-gated ion channel-mediated calcium influx in differentiated PC12 cells with tunable neuromodulation efficiency. In rats, nanotransducer-mediated stimulation of the motor cortex elicits robust electrocorticographic (ECoG) responses accompanied by region-specific electromyographic (EMG) readouts from forelimb, hindlimb, and tail movements. c-Fos staining further verifies strong neuronal activation at stimualtion sites, reaching levels comparable to those induced by invasive electrode-based stimulation. Short- and long-term histological evaluations show no neuronal loss or increase in astrocytic or microglial densities, demonstrating favorable biocompatibility and neural safety. Overall, the proposed transgene-free and minimally invasive nanotransducer approach can generate effective ultrasound-driven neuromodulation, highlighting its potential as a viable alternative for therapeutic neuromodulation.