In Vivo Optogenetics Based on Heavy Metal-Free Photon Upconversion Nanoparticles

Photon upconversion (UC) from red or near-infrared (NIR) light to blue light is promising for in vivo optogenetics. However, the examples of in vivo optogenetics have been limited to lanthanide inorganic UC nanoparticles, and there have been no examples of optogenetics without using heavy metals. Here the first example of in vivo optogenetics using biocompatible heavy metal-free TTA-UC nanoemulsions is shown. A new organic TADF sensitizer, a boron difluoride curcuminoid derivative modified with a bromo group, can promote intersystem crossing to the excited triplet state, significantly improving TTA-UC efficiency. The TTA-UC nanoparticles formed from biocompatible surfactants and methyl oleate acquire water dispersibility and remarkable oxygen tolerance. By combining with genome engineering technology using the blue light-responding photoactivatable Cre-recombinase (PA-Cre), TTA-UC nanoparticles promote Cre-reporter EGFP expression in neurons in vitro and in vivo. The results open new opportunities toward deep-tissue control of neural activities based on heavy metal-free fully organic UC systems. In vivo, optogenetics using photon upconversion (TTA-UC) based on triplet-triplet annihilation is demonstrated. The modification of a thermally-activated delayed fluorescence (TADF) sensitizer with a bromo group promotes intersystem crossing and enables high TTA-UC efficiency at weak excitation light intensities even without using heavy metals. Air-stable UC nanoparticles exhibiting red-to-blue TTA-UC induce EGFP expression in the mouse brain. image