Ultrasound-Triggered In Situ Photon Emission for Noninvasive Optogenetics

Abstract

Optogenetics has revolutionized neuroscience understanding by allowing spatiotemporal control over cell-type specific neurons in neural circuits. However, the sluggish development of noninvasive photon delivery in the brain has limited the clinical application of optogenetics. Focused ultrasound (FUS)-derived mechanoluminescence has emerged as a promising tool for in situ photon emission, but there is not yet a biocompatible liquid-phase mechanoluminescence system for spatiotemporal optogenetics. To achieve noninvasive optogenetics with a high temporal resolution and desirable biocompatibility, we have developed liposome (Lipo@IR780/L012) nanoparticles for FUS-triggered mechanoluminescence in brain photon delivery. Synchronized and stable blue light emission was generated in solution under FUS irradiation due to the cascade reactions in liposomes. In vitro tests revealed that Lipo@IR780/L012 could be triggered by FUS for light emission at different stimulation frequencies, resulting in activation of opsin-expressing spiking HEK cells under the FUS irradiation. In vivo optogenetic stimulation further demonstrated that motor cortex neurons could be noninvasively and reversibly activated under the repetitive FUS irradiation after intravenous injection of lipid nanoparticles to achieve limb movements.

Hydrophobicity Regulation of Energy Acceptors Confined in Mesoporous Silica Enabled Reversible Activation of Optogenetics for Closed-Loop Glycemic Control

“…It has been reported that benzoboric acid can reversibly react with glucose to generate cyclic boronate esters, and the equilibrium shift is dependent on glucose concentrations. 20 The FITC-BA molecule herein exhibits hydrophobic properties attributed its matric moiety fluorescein isothiocyanate and can be changed to hydrophilic FITC-Glu upon exposure to high glucose concentrations. This transformation also can be reversed under lower concentrations of glucose.…”

“…Importantly, to achieve reusable and reversible sensing of glucose, a mesoporous silica layer with proper thickness was coated onto the surface of NaYF 4 :Yb/Tm nanoparticles, in which benzoboric acid-modified fluorescein molecules (FITC-BA) could migrate inward and outward in the mesoporous silica layer to vary energy transfer efficiency and modulate the upconverted blue light intensity. It has been reported that benzoboric acid can reversibly react with glucose to generate cyclic boronate esters, and the equilibrium shift is dependent on glucose concentrations . The FITC-BA molecule herein exhibits hydrophobic properties attributed its matric moiety fluorescein isothiocyanate and can be changed to hydrophilic FITC-Glu upon exposure to high glucose concentrations.…”

“…Recently, lots of luminescent nanomaterials, such as lanthanide-doped upconversion nanoparticles (UCNPs), , scintillants, quaternary oxysulfides, graphene, and liposomes, have been broadly used as light transducers to activate photosensitive proteins through near-infrared light, X-ray, or magnetic forces with deeper tissue penetration to realize noninvasive and tether-free optogenetic applications. , However, a major challenge remains that they provide little or even no control over the strength, timing, or cellular context of the therapeutic effect through a closed-loop regulation . Overexpression of therapeutic gene products with a narrow therapeutic window may be toxic, and excessive activation can be fatal. , Taking diabetes as an example, which is a well-known chronic disease that currently affects over 460 million people worldwide, patients need to monitor the daily blood glucose and inject insulin at meal times to maintain the homeostasis of their glucose levels.…”

Nanotransducer-Enabled Deep-Brain Neuromodulation with NIR-II Light

“…( d ) Transcranial optogenetics based on the red-shifted opsin, ChRmine . ( e ) Sono-optogenetics based on transcranial FUS and circulation-delivered MLNPs. ,, ( f ) Tether-free NIR-II photothermal neuromodulation based on MINDS and TRPV1. Adapted with permission from ref .…”

“…In addition, another non-invasive optogenetics approach, sono-optogenetics, is enabled by circulation-delivered nanoscopic light sources (Figure e). ,− Specifically, Wu et al designed and synthesized ZnS-based mechano­luminescent nanoparticles (MLNPs) that can be activated by deep-penetrating focused ultrasound (FUS) . Upon systemic delivery, these MNLPs flow through the entire body, but only emit 470 nm light transiently at the ultrasound focus in the brain.…”