While offering high-precision control of neural circuits, optogenetics is hampered by the necessity to implant fiber-optic waveguides in order to deliver photons to genetically engineered light-gated neurons in the brain. Unlike laser light, X-rays freely pass biological barriers. Here we show that radioluminescent Gd2(WO4)3:Eu nanoparticles, which absorb external X-rays energy and then downconvert it into optical photons with wavelengths of ∼610 nm, can be used for the transcranial stimulation of cortical neurons expressing red-shifted, ∼590–630 nm, channelrhodopsin ReaChR, thereby promoting optogenetic neural control to the practical implementation of minimally invasive wireless deep brain stimulation.

Fluorescence‐guided surgery (FGS) is routinely utilized in clinical centers around the world, whereas the combination of FGS and photodynamic therapy (PDT) has yet to reach clinical implementation and remains an active area of translational investigations. Two significant challenges to the clinical translation of PDT for brain cancer are as follows: (1) Limited light penetration depth in brain tissues and (2) Poor selectivity and delivery of the appropriate photosensitizers. To address these shortcomings, we developed nanoliposomal protoporphyrin IX (Nal‐PpIX) and nanoliposomal benzoporphyrin derivative (Nal‐BPD) and then evaluated their photodynamic effects as a function of depth in tissue and light fluence using rat brains. Although red light penetration depth (defined as the depth at which the incident optical energy drops to 1/e, ~37%) is typically a few millimeters in tissues, we demonstrated that the remaining optical energy could induce PDT effects up to 2 cm within brain tissues. Photobleaching and singlet oxygen yield studies between Nal‐BPD and Nal‐PpIX suggest that deep‐tissue PDT (>1 cm) is more effective when using Nal‐BPD. These findings indicate that Nal‐BPD‐PDT is more likely to generate cytotoxic effects deep within the brain and allow for the treatment of brain invading tumor cells centimeters away from the main, resectable tumor mass.

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The benefits of contrast‐enhancing imaging probes have become apparent over the past decade. However, there is a gap in the literature when it comes to the assessment of the phototoxic potential of imaging probes and systems emitting visible and/or near‐infrared radiation. The primary mechanism of fluorescent agent phototoxicity is thought to involve the production of reactive molecular species (RMS), yet little has been published on the best practices for safety evaluation of RMS production levels for clinical products. We have proposed methods involving a cell‐free assay to quantify singlet oxygen [(SO) a known RMS] generation of imaging probes, and performed testing of Indocyanine Green (ICG), Proflavine, Methylene Blue, IR700 and IR800 at clinically relevant concentrations and radiant exposures. Results indicated that SO production from IR800 and ICG were more than two orders of magnitude below that of the known SO generator Rose Bengal. Methylene Blue and IR700 produced much higher SO levels than ICG and IR800. These results were in good agreement with data from the literature. While agents that exhibit spectral overlap with the assay may be more prone to errors, our tests for one of these agents (Proflavine) appeared robust. Overall, our results indicate that this methodology shows promise for assessing the phototoxic potential of fluorophores due to SO production.

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