Ultrasound-Induced Cascade Amplification in Mechanoluminescent Nanotransducer for Sono-Optogenetic Deep Brain Stimulation

Remote and minimally invasive neuromodulation is a promising approach in the advent of clinical applications. Ultrasound-triggered mechanoluminescent technology offers a promising approach for achieving remote brain modulation. However, its application has thus far been limited to shallow brain depths due to challenges related to low sonochemical reaction efficiency and restricted photon yields. Here we report a self-amplifying mechanoluminescent nanotransducer based on cascade reactions in liposomes to achieve efficient light emission upon ultrasound stimulation. As a result, blue light was generated under ultrasound stimulation with subsecond response latency. Leveraging the high energy transfer efficiency of focused ultrasound in brain tissue and the high sensitivity to ultrasound of these mechanoluminescent nanotransducers, we are able to show efficient photon delivery and activation of ChR2 expressing neurons in both the superficial motor cortex and deep ventral tegmental area (VTA). Our novel liposome nanotransducers enable minimally invasive deep brain stimulation for behavioral control in animals via a flexible, mechanoluminescent sono-optogenetic system.