Advanced Photonics, Volume. 7, Issue 5, 054001(2025)

Optogenetic technology: breakthroughs and challenges from basic research to clinical translation

Hongyou Zhao1、*, Hui Yue2, Wenxin Chou1, Shanlin Yang3, Yidi Liu3, Mianwang He4, Yunqi Li5, Jianfei Guo2, Haixia Qiu3、*, Yilei Xiao2、*, and Ying Gu1,3、*
Author Affiliations
  • 1Beijing Institute of Technology, School of Medical Technology, Beijing, China
  • 2Liaocheng People’s Hospital, Department of Neurosurgery, Liaocheng, China
  • 3Chinese PLA General Hospital, The First Medical Centre, Department of Laser Medicine, Beijing, China
  • 4Neurology Department of Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China
  • 5Chinese PLA General Hospital, The First Medical Centre, Department of Gastroenterology, Beijing, China
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    Figures & Tables(18)
    Historical development of optogenetics. Left to right: 1970s - reproduced from Ref. 6 with permission; © 2018, Elsevier. 2005 - reproduced from Ref. 1 with permission; © 2005, Nature Portfolio. 2007 - reproduced from Ref. 7 with permission; © 2007, IOP Publishing. 2010 - reproduced from Ref. 8 with permission; © 2007, Nature Portfolio. 2012 - reproduced from Ref. 9, under CC-BY license. 2022 - reproduced from Ref. 10 with permission; © 2022, Nature Portfolio. 2024 - reproduced from Ref. 11, under CC-BY license.
    Schematic representation of two classic photosensitive proteins. (a) Under 470 nm blue light irradiation, the ion channel gate of the photosensitive protein ChR2 opens, relieving the hindrance to cations such as Na+ and Ca2+ from entering the cell and causing depolarization. (b) Under 589 nm blue light irradiation, the photosensitive protein NpHR causes isomerization of retinal, leading to active transport of Cl− and resulting in cell hyperpolarization.
    Schematic illustration of the application of optogenetic technology in different diseases. Left: light stimulation triggers neurons’ depolarization for the treatment of diseases in different systems. Right: light stimulation triggers neurons’ hyperpolarization for the treatment of diseases in different systems.
    Photogenetic therapy promotes relief of AD symptoms. (a) Experimental scheme regarding optogenetic activation of neurons. (b) ORM function of mice with and without laser conditions. (c) Motor function of mice with and without light conditions. (a)–(c) Reproduced from Ref. 80, under CC-BY license. (d) Simulation diagram of LOCa. The LOV2 structure is coupled with the ORAI1 structure, and in a dark environment, this domain is in a closed state. When exposed to blue light (470 nm), the conformation of LOV2 changes, causing a conformational change in ORAI1, which in turn triggers the transmembrane flow of Ca2+. (e) Schematic representation of the structure and calcium ion changes in LOCa3. (f) Expressing LOCa3 in Drosophila. The GAL4-UAS expression system binds to AD fruit flies with Aβ42 or LOCa3, with GAL4 as the driver gene and elav as the promoter. (d)–(f) Reproduced from Ref. 43, under CC-BY license.
    Research on the mechanism and function of photogenetic technology in IS. (a) Schematic diagram of photoactivation of astrocytes to protect the BBB from IS damage. Reproduced from Ref. 105, under CC-BY license. (b) 40 Hz optogenetic stimulation mechanism diagram (upper left). The discharge frequency of different groups and the gamma oscillation trajectory in M1. Reproduced from Ref. 106, under CC-BY license.
    Photogenetic therapy improves symptoms of epilepsy. (a) Experimental protocol and timeline for photostimulation therapy. (b) Duration of electrographic seizures in different groups of mice with and without light stimulation. (c) Duration of epileptic seizures in different groups of mice with and without light stimulation. Reproduced from Ref. 45, under CC-BY license.
    Optogenetic stimulation promotes limb function recovery after SCI.(a) Analysis of hind limbs during treadmill exercise with swinging (light gray), standing (dark gray), and light stimulation. The lower right corner shows the correct and incorrect placement of hind limbs (top), the horizontal ladder test (middle), and the horizontal ladder test used to evaluate the motor function in the eighth and tenth weeks. Reproduced from Ref. 130, under CC-BY license. (b) Schematic diagram of wireless optoelectronic system (upper left). CT reconstruction and MRI with or without device implantation (upper right). Wireless closed-loop optoelectronic system (lower left). The impact of this system on mouse movement (lower right). Reproduced from Ref. 131 with permission; © 2022, Nature Portfolio.
    Development of advanced cardiac biointerfaces for the treatment of arrhythmia. (a) Schematic diagram of a graphene electrode array coupled with the heart. (b), (c) The graphene electrode array demonstrates the capacity to record signals and stimulate heart tissue and to rectify arrhythmia subsequent to light stimulation. SA node, sinoatrial node; AV node, atrioventricular node. Reproduced from Ref. 146, under CC-BY license.
    Research on the regulatory effect of FOS on muscles. (a) Experimental framework for muscle characterization and control. (b) Mouse muscle stimulation platform. (c) Example of acquired muscle force signals under FOS and FES. Reproduced from Ref. 148 with permission; © 2024, AAAS.
    Acousto-optic genetics device. (a), (b) Ultrasound-mediated light emission. (b) Mouse muscle stimulation platform. (c) Thy1-ChR2 YFP mice (top) and wild-type mice (bottom) during acoustic light stimulation before and after injection of ZnS nanoparticles. (d) Statistics of hind limb displacement in different groups of mice before and after FUS stimulation (n=3 per group). The bar heights indicate the mean; error bars indicate SEM. ****P<0.0001; N.S., not significant. Reproduced from Ref. 150 with permission; © 2020, AAAS.
    Photogenetic technology for cancer treatment. (a) Schematic representation of LiPOP channel proteins. (b) In vivo killing of HeLa tumor cells in mice by LiPOP1, when applied in combination with UCNP, was observed. (c) Western blot results. Reproduced from Ref. 161, under CC-BY license. (d) Schematic diagram of experimental principle. (e) Changes in cytokine content in response to light stimulation. Left to right: IFN-β, TNF-α, IL-12. (f) Kaplan–Meier curves for mouse survival. Reproduced from Ref. 162, under CC-BY license.
    Research on the inhibition of nerve impulses in neurodegenerative diseases. (a) Under 560 nm light stimulation, neurons expressing only HALO were silenced (left). Analysis of animal laterality (right). Reproduced from Ref. 183 with permission; © 2015, Nature Portfolio. (b) Experimental plan (top) and time-frequency heatmap of ArchT suppression (bottom). Reproduced from Ref. 184, under CC-BY license. (c) Schematic showing closed-loop seizure detection and light delivery to activate the inhibitory opsin stGtACR2 in PCP4-Cre mice (left). Potential diagram of epileptic mice transfected with stGtACR2 inhibitory photosensitive protein under light and non-light conditions (right). Reproduced from Ref. 42 with permission; © 2024, Nature Portfolio.
    Photogenetic technology suppresses nerve impulses and treats multiple diseases. (a) Schematic of NpHR virus injection location. (b) ChR2 virus injection location and fiber optic insertion location. Reproduced from Ref. 195, under CC-BY license. (c) Schematic diagram of the polysynthetic central pathway. Reproduced from Ref. 53, under CC-BY license.
    Wireless self-powered optogenetic modulation system for treating arrhythmia. (a) Wireless self-powered optogenetic system for heart protection after MI. (b) Fluorescence imaging and quantitative analysis of c-fos and NGF after treatment. (c) Quantitative analysis of LSG neural activity images from different groups, as well as corresponding image amplitudes and frequencies. Reproduced from Ref. 205, under CC-BY license.
    Optogenetic stimulation for visual restoration. (a) Experimental setup. (b), (c) Visual detection task and EEG data decoding. Reproduced from Ref. 21 with permission; © 2021, Nature Portfolio.
    Optical amplifier equipment. (a) The combination of genetically modified cells (purple circles) in the eye and OLED microdisplay. (b), (c) Single-stack and tandem-stack OLED structure diagrams. (d) Stability measurement of single-stack and tandem-stack equipment of different models operating under fixed voltage pulses (12.5 Hz, 20% duty cycle); the inset shows a silicon substrate with OLED devices of different sizes and a heat sink. Reproduced from Ref. 214, under CC-BY license.
    • Table 1. Properties of various photosensitive proteins.*

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      Table 1. Properties of various photosensitive proteins.*

      FunctionOpsinMechanismPA (nm)OK (ms)EEPD (nm)Reference
      MLA (%)EL (%)
      Excitatory photosensitive proteinsChR2Cation channel46010≥901000.5 to 1.01
      ChR2 (H134R)Cation channel46018≥90100 to 1100.5 to 1.030,31
      ChIEFCation channel45010≥85%90 to 1000.5 to 1.032
      ChRGRCation channel5054 to 8<5050 to 701.0 to 2.033
      VChR1Cation channel54513350 to 6040 to 600.5 to 1.034
      C1V1Cation channel54015660 to 7060 to 801.0 to 2.035
      C1V1 ChETA (E162T)Cation channel5305880 to 9090 to 1001.0 to 2.036
      soCoChRCation channel480<1≥90120 to 1500.5 to 1.037
      ChronosCation channel480<1>8090 to 1000.5 to 1.038
      ReaChRCation channel590 to 6302.470 to 8070 to 802.0 to 3.039
      Inhibitory photosensitive proteinseNpHR3.0Chloride ion channel5904.2≥90150 to 2001 to 20040
      Arch/ArchTProton pump566980 to 9080 to 1201 to 10021
      MacProton pump47060 to 8060 to 901 to 10021
      eBRProton pump5401970 to 8070 to 1001 to 10040
      JawsProton pump6351875 to 8590 to 1101 to 16041
      stGtACR2Ion channel593≥90120 to 1501 to 10042
    • Table 2. Summary of optogenetics applied in various systems of the body.*

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      Table 2. Summary of optogenetics applied in various systems of the body.*

      SystemsOrgansDiseasesPhotosensitive proteinsProtein-expressing cellsApplicationsReferences
      Nervous systemBrainADeNpHR3.0, ChR2, LOCa3ET neurons, hilar GABAergic neurons, etc.T, M43, 75, 80, 173, 224, 225
      PDChR2, NpHR, mtACR, HALOZI GABAergic neurons, MesDA neurons, etc.T, M44, 180, 183, 226, 227
      ISChR2Astrocytes, M1 interneurons, etc.T, M46, 105, 106, 228
      EpilepsyChR2, ArchT, NpHR, stGtACR2MSGNs, FC neurons, HONs, etc.T, M42, 45, 123, 184
      Spinal cordSCIChR2Spinal cord neurons, etc.T, E130, 131, 229
      EyeRPChrimsonRRGCs, etc.T, M, and E24, 208, 211, 212, 230234
      Circulatory systemHeartCardiac arrhythmiasChR2, ArchTLSG neurons, etc.T, M, and E14, 146, 205, 235
      Immune systemSkin, etc.CancerLiPOP, FLICsDifferent tumor cellsT5557, 161, 162
      Urinary systemKidneyCKDChR2, NpHRMultiple types of neuronal cellsT, M53, 236238
      Locomotor systemMuscleMuscle controlChR2Muscle cellsM148, 239, 240
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    Hongyou Zhao, Hui Yue, Wenxin Chou, Shanlin Yang, Yidi Liu, Mianwang He, Yunqi Li, Jianfei Guo, Haixia Qiu, Yilei Xiao, Ying Gu, "Optogenetic technology: breakthroughs and challenges from basic research to clinical translation," Adv. Photon. 7, 054001 (2025)

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    Paper Information

    Category: Reviews

    Received: Apr. 21, 2025

    Accepted: Jul. 17, 2025

    Posted: Jul. 17, 2025

    Published Online: Aug. 22, 2025

    The Author Email: Hongyou Zhao (zhaohy@bit.edu.cn), Haixia Qiu (qiuhxref@126.com), Yilei Xiao (yileixiao@163.com), Ying Gu (guyinglaser301@163.com)

    DOI:10.1117/1.AP.7.5.054001

    CSTR:32187.14.1.AP.7.5.054001

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