Tailoring nanocrystals as a versatile platform for noninvasive neuroengineering

PROJECT SUMMARY Deep brain stimulation (DBS) has been a cornerstone in treating neurological disorders, utilizing electrical impulses to target deep brain structures. While effective, DBS is limited by its invasive nature and inability to selectively target specific cell types. Optogenetics offers unparalleled cellular precision but is constrained by the penetration depth of visible light in biological tissue. To address these challenges, we propose a novel approach using nanomaterial-mediated photon conversion to create a fully noninvasive, cell specific technological platform for modulating various structures in the nervous system. This approach centers on molecularly engineered, intravenously delivered nanocrystals capable of converting tissue-penetrating stimuli into visible light, thereby enabling precise optogenetic control over targeted cells. While our prior efforts employed upconversion nanoparticles (UCNPs) for near-infrared (NIR)-to visible light conversion, their low upconversion efficiency and invasive delivery significantly hindered the application. To overcome these limitations, we will adopt a multifaceted strategy. By molecularly tailoring ultra-bright UCNPs, we will push transcranial NIR upconversion optogenetics to unprecedented depth in the deep brain. By employing focused ultrasound-assisted blood-brain barrier (BBB) opening, we will intravenously deliver the nanocrystals to target tissues, achieving full noninvasiveness. By leveraging nanoscintillators that can convert X-ray to visible light, we will develop X-ray scintillation optogenetics that can offer unparalleled stimulation depth. We will also showcase how our new technology may go beyond brain neurons and modulate diverse structures in the nervous system that are conventionally hard to reach. Overall, our nanomaterial-based platform offers novel approaches to remotely modulate various neural components across species with unprecedented depth and precision, holding the potential for developing next- generation noninvasive neurological treatments.