Seeing the Sound: An Ultrasound-Mediated Intravascular Light Source enabled by Colloidal Mechanoluminescent Materials

Light is used in a wide range of methods in biology and medicine, such as fluorescence imaging, optogenetics, photoactivatable gene editing, photothermal and photodynamic therapies to treat cancers, and photochemotherapy to inactivate viruses <i>in vivo</i>. A critical challenge of applying light <i>in vivo</i>, such as deep-brain optogenetic neuromodulation and photochemotherapy in deep organs, arises from the poor penetration of photons in biological tissue due to scattering and absorption. Therefore, delivering light deep into the body requires invasive procedures, such as the insertion of optical fibers and endoscopes, as well as surgical removal of overlying tissues. The very invasiveness of these procedures also precludes easy repositioning and volume adjustment of the illuminated region in the same subject. To address these challenges, our lab has developed an ultrasound-mediated intravascular light source, leveraging the deep-tissue penetration of focused ultrasound. We capitalized on mechanoluminescent nanotransducers (MLNTs), which are colloidal nanoparticles of mechanoluminescent materials synthesized via a biomineral-inspired suppressed dissolution approach. These MLNTs can be delivered intravenously into blood circulation and emit light locally at the ultrasound focus. Owing to the deep penetration and fast temporal kinetics of ultrasound, we have demonstrated that this method can produce on-demand and dynamically programmable light emission patterns at elevated depths in different organs of live mice with millisecond precision. This ultrasound-mediated intravascular light source has allowed us to perform noninvasive “sono-optogenetic” neuromodulation in live mice, as well as brain-wide “scanning optogenetics” that activate different brain regions of the same mouse brain. Our development of the ultrasound-mediated intravascular light source has been published in <i>PNAS</i> (2019), <i>Science</i> (2020), <i>Science Advances</i> (2022), <i>JACS</i> (2022), <i>JACS</i> (2023), and <i>Nature Protocols</i> (2023).