Optogenetics is a subject that combines optics and genetics to precisely regulate neural activity and behavior.1^,2 The advent of optogenetics offers a novel technique for investigating the neural functions of the brain and treating neurological diseases.3^–5 The beginning of optogenetics can be traced back to the 1970s, with four types of rhodopsins discovered in the saline archaebacterium Halobacterium salinarum: the green-light-driven proton pump bacteriorhodopsin (BR), the orange-light-driven chloride pumps halorhodopsins (Halo), and the light-sensitive receptor sensory rhodopsins I and II (Fig. 1).12^–14 The photosensitive receptors, sensory rhodopsins I and II, are widely distributed in archaea, bacteria, fungi, and algae for photosynthesis and signaling. Nevertheless, these rhodopsins only effectively work in a high-salt environment.13^,14

In 2002, Nagel et al. discovered channelrhodopsin-1(ChR1) in green algae.15 ChR1 is a type of microbial opsin. The hydrophobic core region of ChR1 shares homology with light-activated proton pump bacterial rhodopsin. ChR1 produces proton-selective photo-gated conductance when it is expressed in Xenopus laevis oocytes.15 In the next year, channelrhodopsin-2 (ChR2) was first expressed in mammalian cells and demonstrated to be a photoswitchable cation-selective ion channel, which can induce cellular response to blue light stimulation at ∼460nm.16 In 2005, Boyden et al. successfully achieved reliable millisecond-level control of neural spikes as well as excitatory and inhibitory synaptic transmission in hippocampal neurons by integrating lentiviral gene delivery with high-speed optical switches.1 The expression of ChR2 exhibited minimal effects on neuronal electrical properties and cell survival, providing precise manipulation tools for applications in neuroscience and biomedical engineering, which was a breakthrough in the establishment of optogenetics.1 In 2007, Aravanis et al.7 developed a functional optical neural interface through regulating ChR2 expression by the CaMKIIα promoter in neurons. Combined with a fiber optic cable with a diameter of ∼200μm to conduct 473 nm blue light, quantifiable whisker deflection behavior was successfully induced in rats and mice.7 This technology overcomes the nonspecific limitations of traditional electrode stimulation on cell types and provides precise spatiotemporal manipulation tools for neuroscience research and future clinical applications. In the same year, Zhang et al.8 identified the archaeal light-driven chloride pump (NpHR) as an optogenetic tool for the first time, which can accurately optically inhibit neural activity. This study further demonstrated that NpHR and ChR2 can form a complete system to control neural activity bidirectionally. The light-induced allosteric gating mechanisms of ChR2 and NpHR both use all-trans retinal as the chromophore, triggering conformational changes by absorbing photons of specific wavelengths (Fig. 2).1^,8 ChR2 rapidly isomerizes from all trans to 13 cis under 470 nm blue light irradiation, triggering cascade displacement of transmembrane helices (especially S1 to S4 helices), breaking internal hydrogen bonds and salt bridge networks, and rearranging key amino acid residues (e.g., T252, Y253) in channels to form hydrophilic pathways with a diameter of ∼5Å, which allows Na+/Ca2+ influx and results in neuronal depolarization.17^–19

NpHR is sensitive to yellow light. The isomerization of retinal drives the rotation of the proton pump domain under 589 nm blue light irradiation, exposing the Cl− binding site. Cl− influx is mediated through the proton gradient coupling mechanism, causing neuronal hyperpolarization.7 The conformational essence of ChR2 and NpHR is the energy conversion of light, but they achieve functional differentiation of cation activation or anion inhibition through different transmembrane structural recombination (helical displacement and domain rotation), providing complementary neural regulatory tools for optogenetics.20

In 2010, Chow et al. identified the yellow light-driven archaetodopsin-3 (Arch) and blue light-driven Leptosphaeria maculans fungal opsins (Mac) proton pumps and demonstrated that these two proteins have a more pronounced neural silencing effect than that of NpHR.21 In the same year, Kravitz et al.22 selectively expressed ChR2 in medium spiny projection neurons (MSNs) of the mouse striatum along both direct and indirect pathways using Cre-dependent viral vectors. Their findings revealed that bilateral optogenetic activation of indirect-pathway MSNs induced a Parkinson-like state, characterized by increased freezing behavior, bradykinesia, and reduced locomotor initiation. Conversely, the activation of direct-pathway MSNs not only enhanced locomotion in normal mice but also completely rescued motor deficits in a 6-OHDA mouse model of Parkinson’s disease (PD). In 2012, Liu et al.23 expressed ChR2 in target neurons involved in memory traces in the hippocampus of mice, which could activate neurons and awaken specific memories of mice after blue light exposure. In 2018, upconversion nanoparticles (UCNPs) were first applied in optogenetics and significantly improved the depth of neuronal activity manipulation of optogenetics technology in the brain of mice.9 In 2021, optogenetic technology was successfully applied to the treatment of retinitis pigmentosa (RP) in a patient and partially restored the patient’s vision.24 This is the first report that optogenetics has been applied to the treatment of human disease. Besides Ca2+ and Na+, K+ is also a critical ion in the electrophysiological activity of the nervous system. In 2022, Govorunova et al.10 extracted natural kalium channelrhodopsin (KCR) from Hyphochytrium catenoides and found that KCR was a channelrhodopsin (ChR) with higher selectivity for K+ over Na+, which provides a basis for the study and treatment of some neural diseases involving K+ channels. In 2024, Kashyap et al.11 developed a technique for photo-controlled release of single molecules in cells, which provides a new method for single-molecule imaging of membrane proteins and cytoplasmic proteins in living cells. Today, optogenetic technology has been widely applied to treat various diseases. According to the pathogenesis of the diseases, optogenetic technology was used to activate or inhibit neural impulses to correct the abnormal neural activity and achieve the goal of treating diseases.

In this review, we summarize the recent progress of optogenetic technology in biomedical applications, including the activation of nerve impulses to treat central nervous system diseases, digestive system diseases, locomotor system diseases, and cancer; or the inhibition of nerve impulses to treat central nervous system diseases, circulatory system diseases, urinary system diseases, and others (Fig. 3). Moreover, the research and clinical translation of optogenetic technology in optic nervous system is highlighted. Finally, the challenges and future prospects of the translation of optogenetic technology to the clinic are discussed.

Photosensitive proteins are the core components of optogenetic technology, which can be divided into two types: excitatory photosensitive proteins and inhibitory photosensitive proteins. ChR2,25 one of the excitatory photosensitive proteins, is capable of causing depolarization of cell membranes and neuronal excitation under blue light irradiation. NpHR,26 one of the inhibitory photosensitive proteins, can induce hyperpolarization of cell membranes and inhibit nerve impulses under yellow-green light irradiation. These two classic photosensitive proteins have been extensively applied in numerous studies, yet the expression of them in target cells still relies on viral vector-mediated transfection or transgenic technologies for gene delivery, which inherently leads to problems such as inconsistent expression efficiency, potential immunogenicity, and inter-individual variability.2^,27 Furthermore, the tissue penetration depth of 460 nm (blue) and 590 nm (yellow) light remains constrained.28 For deep-tissue stimulation, fiber-optic implantation remains indispensable. However, this approach introduces optical artifacts wherein light scattering-induced spot deviation often causes unintended activation of adjacent nontarget neurons, thereby compromising the spatiotemporal precision of experimental outcomes.29 Besides ChR2 and NpHR, more photosensitive proteins with different properties that can regulate neural activity have also been found and developed (Table 1). These photosensitive proteins have been widely applied in investigation or treatment of neurological disorders,43^–46 alimentary system diseases,47^–50 circulatory system diseases,51^,52 urinary system diseases,53^,54 cancer,55^–57 and so on.

Neurological diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke (IS), have caused more concern due to their rising incidence and earlier age of onset.58 Spinal cord injury (SCI) and cerebrovascular diseases seriously affect the quality of life and mental health of patients and their families.59^–62 The primary etiology of these diseases is the impairment or deficiency of neuronal function, which ultimately results in the deterioration of bodily functions.63^,64 Optogenetic technology mediated by excitatory photosensitive proteins enables precise activation of neurons.1^,2 Many studies have demonstrated that optogenetic technology plays a role in the study or treatment of the above diseases.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease with the characteristics of insidious onset and progressive development. The main symptoms are memory impairment; the decline of language and cognitive function, which leads to a decrease in the patient’s daily life abilities; and mental and behavioral abnormalities, adding a significant burden on the family and society.65 The number of individuals diagnosed with AD worldwide has reached 50 million, and it is estimated that this number will increase to 152 million by 2050.66 Therefore, it is urgent to develop effective interventions for AD.

Optogenetic technology is a novel approach for the research and treatment of AD. In 2011, Bell et al.67 employed optogenetics and other techniques to conduct a study on the CA1 region of the hippocampus. Their research revealed that the release of acetylcholine predominantly activates the α4 and β2 subunits (α4β2*) of nicotinic receptors in interneurons, thereby generating excitatory postsynaptic potentials.67 They accurately identified the location and electrophysiological characteristics of the interneurons responsible for generating this potential. Amyloid-β (Aβ) is the main feature of AD and has a high affinity for α4β2* receptors, thus providing a basis for the study of AD.68 Suberbielle et al.69 explored the pathogenesis of AD at the molecular level through optogenetic technology. They found that physiologic brain activity causes DNA double-strand breaks (DSBs) in neurons, with exacerbation by Aβ exacerbating neuronal DSBs, which subsequently impacts gene expression and cognitive function.69 This discovery offered a novel target for the treatment of AD.

Memory impairment caused by AD is a problem that scientists have been trying to overcome. Dranias et al.70 studied the memory mechanism through optogenetic technology in 2013. The results demonstrated that the in vitro cultured discrete cortical neuronal network exhibits short-term memory capacity. Notably, the network burst has a dual impact on memory, which offers valuable insights for the research on memory impairment in AD.70 Previous studies have shown that adenosine A2A receptor (A2aR) in the hippocampus is associated with memory deficits in AD.71 Li et al.72 integrated optogenetic technology to precisely modulate the A2aR signal. Their findings verified that the activation of the A2aR signal in the hippocampus can induce cAMP and phosphorylated-CREB (p-CREB) signals, thereby leading to memory deficits.72 This provides a novel theoretical basis for the treatment of memory impairment. In 2018, Yang et al.73 disclosed the mechanism underlying the spatial learning and memory impairments in AD mice, which were induced by the degeneration of the ECIIPN−CA1PV pathway through the application of optogenetics.73 This discovery has furnished a novel signaling pathway for the exploration of memory deficits in AD. Subsequently, in 2019, Etter et al.74 restored slow gamma oscillations in the hippocampus of AD mice through optogenetic stimulation, which reversed memory loss and provided support for the role of slow gamma oscillations in spatial memory retrieval. Nevertheless, fiber optic implantation damage and light attenuation are obvious drawbacks of traditional optogenetics. Fortunately, the emergence of the new photosensitive protein SOUL provides a tool to overcome these problems. It was demonstrated that transcranial light stimulation was able to effectively activate SOUL-expressing neurons in the deep brain regions of animals and prolong the activation state. Therefore, the high sensitivity of SOUL provided the basis for noninvasive operation.75

Memory loss and cognitive impairment of AD are associated with dysfunction of the prefrontal cortex, particularly object recognition memory (ORM).76^,77 Previous studies have demonstrated that the extratelencephalic projection (ET) neurons in the prefrontal cortex (PFC) play a crucial role in short-term memory.35^,78 However, the mechanism linking the dysfunction of ET neurons and the impairment of object recognition memory remains elusive.79 Sun et al.80 expressed ChR2 in the ET neurons within the PFC of mice and activated these neurons through blue light stimulation under specific conditions [Fig. 4(a)]. The results showed that light stimulation significantly increased the improvement of motor function and ORM function in AD mice [Figs. 4(b) and 4(c)]. This study provides a target for the treatment of cognitive dysfunction in AD using optogenetic technology.

The imbalance of calcium ions may be one of the pathological mechanisms of AD.81 To verify this hypothesis, He et al.43 proposed a design of light-controlled calcium channel [LoCa, Fig. 4(d)]. They optimized it by introducing additional mutations multiple times, thereby obtaining LOCa3 with improved physicochemical properties [Fig. 4(e)]. LOCa3 can remarkably augment the calcium ion signals in the Drosophila brain upon light stimulation and ameliorate the loss of climbing ability induced by AD [Fig. 4(f)]. This implies that this channel has the potential to be used in the treatment of AD.

Parkinson’s disease (PD) is the second most prevalent clinical neurodegenerative disease after AD. As estimated by the Global Burden of Disease study of 2016, ∼61 million individuals worldwide are afflicted with this disease.82^,83 The incidence and prevalence of PD have increased rapidly over the past two decades.84

The striatum is a brain region closely related to PD.85 The alpha-synuclein (α-syn) oligomers can affect synaptic function.86^,87 However, the exact role and potential mechanisms by which these oligomers specifically affect synaptic transmission and plasticity in striatal spiny projection neurons (SPN) are still not fully understood. Durante et al.90 combined optogenetics technology with other techniques and conducted research on mice. They found that α-syn damages SPNs in both direct and indirect pathways of the basal ganglia by interacting with the GluN2A N-methyl-D-aspartate receptor.88^,89 This damage further leads to defects in visual-spatial learning.90 Apart from the effect of α-syn on neurons, changes in neuronal activity in the parafascicular nucleus (PF) also play a key role in the development of PD. It was found that the activation of ChR2-expressing PF neurons through optogenetic technology caused an imbalance in the PF-indirect SPNs pathway and motor deficits, whereas chemical inhibition of this pathway improved motor learning ability in PD mice, providing a new strategy for the treatment of PD.91 Besides neuronal dysfunction, astrocytes and mitochondria may be closely related to the development of PD.92^,93 Li et al.94 successfully developed the anion channel rhodopsin mtACR that can regulate mitochondrial membrane potential and verified through various experiments that mitochondrial dysfunction in astrocytes can lead to neurotransmitter imbalance and motor dysfunction, and can induce PD-like phenotype in the long term. Moreover, the mechanisms of sleep disorders and respiratory rhythm abnormalities in PD have been explored through optogenetic technology.95^,96

Ischemic stroke (IS) is a severe neurological disorder that induces significant remodeling of neuronal connections and functions, often resulting in impairments or even fatalities in motor, sensory, and cognitive domains.97 The optogenetic technology can precisely control target nerve cells, which can be used to study the function of cells and signaling pathways in IS, thereby unraveling mechanisms and laying a foundation for treatments.

Many studies have demonstrated that the cortex is the key target in IS research.98^,99 In 2014, Lim et al.100 integrated optogenetic technology with voltage-sensitive dye imaging technology to disclose the alterations in cortical functional connectivity subsequent to IS, thereby laying a theoretical foundation for the treatment and rehabilitation of this condition. This work provided crucial insights into the post-IS cortical changes.100 In the same year, May et al.101 demonstrated for the first time that nonhuman primates can successfully perceive optogenetic stimulation of the somatosensory cortex, which opened up new possibilities for nerve repair strategies after IS. The thalamus, serving as a crucial hub for sensory information transmission, might be implicated in stroke.102 Tennant et al.103 investigated the thalamocortical circuits by means of optogenetic technology. Their results revealed that the excitability of thalamocortical circuits declined following IS. However, light stimulation could augment the function of cortical circuits as well as the limb sensorimotor ability, thus presenting a novel therapeutic strategy for IS.103

Astrocytes are of vital significance in the nervous system, and their activation represents a crucial characteristic of IS.104 To investigate the effect and molecular mechanism of astrocytes on the blood–brain barrier (BBB) in IS, Suo et al.105 treated various subgroups of transgenic rats with GFAP-ChR2-EYFP. Following the administration of blue light stimulation, the activation of astrocytes was observed in rats. The expression level of IL-10 in the treatment group increased, protecting the integrity of the BBB and reducing neuronal apoptosis. This provides a new direction for the treatment of IS by optogenetic technology [Fig. 5(a)].105

Gamma oscillations are related to a multitude of cognitive functions and are capable of facilitating synaptic plasticity. Many studies have clearly demonstrated that gamma oscillations can be disrupted following an IS.107^,108 Hence, driving gamma oscillations might contribute to post-stroke recovery. To explore the mechanism by which the induction of gamma oscillations promotes post-stroke recovery, Wang et al.106 subjected IS mice expressing the ChR2 gene to light-genetic stimulation of varying intensities. After different light stimuli, the firing rate of M1 interneurons was significantly higher under the 40 Hz stimulation. After an IS, the synchronous activity within the neuronal population is disrupted.109 Under slow-gamma oscillations stimulation, interneurons (INs) synchronize with the principal neurons (PNs) that have a slower firing rate. These results suggest that the gamma oscillations induced by the 40 Hz optogenetic stimulation lay a foundation for facilitating the recovery of IS [Fig. 5(b)].106

Epilepsy is a recurrent neurological disorder, which is a clinical manifestation of abnormal, excessive, purposeless, and synchronized neuronal discharges.110 Traditional treatment methods of epilepsy, such as medication and deep brain stimulation (DBS), not only cause side effects but also perform poorly in terms of temporal and spatial resolution, making it difficult to accurately and effectively control the condition.111^–113 The emergence of optogenetic technology has brought new hope for the treatment of epilepsy.114

Among various types of epilepsy, temporal lobe epilepsy (TLE) is the most happened in adults.115 The pathogenesis of TLE is closely related to the neurons in the excitatory circuit of the hippocampus-interneurons (MCs).116 To explore the role of MCs within the context of TLE, Bui et al.117 conducted an experiment wherein they expressed both excitatory and inhibitory photosensitive proteins in transgenic mice. Their results indicated that the presence of MCs was capable of suppressing the onset of TLE via a bidirectional regulatory mechanism.117 In fact, previous studies have shown that activating inhibitory neurons has a positive effect on reducing epileptic seizures.118 Among them, the activation of parvalbumin-positive (PV) neurons in the medial septum has been shown to inhibit the onset of TLE.119 Similarly, Chen et al.120 validated the role of GABAergic neurons in the substantia nigra pars reticulata (SNr) in TLE, identifying the involvement of disinhibitory neural circuits from SNr to the parafascicular nucleus (PF) in regulating epileptic seizures, providing a new potential target for epilepsy treatment. Based on the above study, Hristova et al.45 proposed an innovative TLE treatment strategy, which uses medial septal GABAergic neurons (MSGNs) as an ideal target for stopping epileptic seizures, and validated it through a series of rigorous experiments. The ChR2 gene was successfully expressed in mice via AAV, and the seizures were induced by the delivery of kainate to the dorsal hippocampus [Fig. 6(a)]. Subsequently, the local field potential (LFP) was quantified through the implantation of electrodes into the molecular layer of the dentate gyrus, which is the primary region for regulating the propagation of seizures. The application of light stimulation to the hippocampus resulted in a modulation of the LFP oscillations, which had a positive effect on epilepsy. To ascertain whether the same effect is observable in freely moving mice, a wireless closed-loop optogenetic apparatus equipped with light-emitting diodes (LEDs) was employed. The results demonstrated that the optogenetic stimulation of MSGNs for 30 s at 10 Hz effectively reduced seizure durations when compared with no stimulation in mice injected with AAV expressing mCherry-ChR2 [Figs. 6(b) and 6(c)]. Wireless closed-loop optogenetic stimulation provides a new strategy for TLE therapy.

Previous studies indicated that there is a correlation between epileptic seizures and the interaction of astrocytes and neurons.121^,122 Zhao et al.123 stimulated the primary motor cortex of epileptic mice using light to activate astrocytes expressing ChR2. The results demonstrated a significant reduction in the incidence rate of epilepsy. Furthermore, the cerebellar fastigial nucleus and the deep and intermediate layers of the superior colliculus have been shown to be potential targets for treating epilepsy.124^,125

Spinal cord injury (SCI) is a severe traumatic disorder that often leads to impairments in motor function. It is frequently caused by incidents such as traffic accidents and falls from heights. Promoting axonal regeneration and reducing scar formation are crucial for the restoration of neurological function after SCI.126 Electrical stimulation has been shown to affect the release of inflammatory factors and the differentiation path of stem cells by modulating intracellular signaling pathways.127^,128 However, its application may increase the risk of infection and cause residual effects over time and in specific locations.129 By contrast, optogenetics technology combined with computer systems offers precise spatiotemporal regulation. For example, by coupling photosensitive proteins with glutamatergic neurons in the medulla oblongata of mice, a strong depolarization current is induced upon photoactivation, which significantly contributes to the restoration of motor function in SCI mice [Fig. 7(a)].130 This study clearly demonstrates the potential of optogenetics in SCI treatment. Moreover, the development of suitable wireless optoelectronic interfaces is essential for the functional research of the nervous system. The device developed by Kathe et al.131 can precisely control light pulses, highlighting the importance of advanced interfaces in the application of optogenetics [Fig. 7(b)]. Currently, the majority of SCI research is focused on rodents, with few studies on large animals such as dogs and monkeys.132^,133

Cardiac arrhythmias are among the serious circulatory system diseases. Traditional treatment methods, such as implantable electronic pacemakers and defibrillators, carry the risk of damaging myocardial cells and interfering with normal cardiac electrophysiological activity.134 However, optogenetic technology has the characteristics of high spatiotemporal resolution and strong specificity, which can accurately control myocardial cells and achieve painless and efficient treatment of arrhythmia.

In 2010, optogenetic technology was initially utilized in the research of the heart. Arrenberg et al.135 expressed a variety of photosensitive proteins in zebrafish cardiomyocytes after fertilization, combined with optical tools and other technologies to build a new type of optical pacemaker, which is located in the heart, and simulated a variety of arrhythmias, achieving precise control of cardiac function. In the same year, Bruegmann et al.136 introduced the stimulation effect of optogenetic technology on cardiomyocytes in vivo and in vitro. The results showed that its effect was superior to that of traditional electrical stimulation.136 The animals applied in these two studies, zebrafish and mice, are small animals. Subsequently, Jia et al.137 adopted a tandem cell unit strategy to couple nonexcitable cells harboring photosensitive proteins with myocardial cells of adult dogs and neonatal rats in vitro. Upon light stimulation, a robust depolarization current was generated, leading to an enhancement in the light excitation efficiency. This advancement addressed some of the limitations of previous studies and brought the field closer to practical applications. Short QT syndrome (SQTS) is an electrocardiogram dysfunction syndrome due to the shortening of the cardiac action potential (AP).138 Traditional treatment methods such as implantable cardioverter-defibrillator (ICD) have high complications.139 In 2014, Karathanos et al.140 used a computational model to assess the feasibility of optogenetic treatment of shortened AP in SQTS. In an ideal situation, optogenetic therapy has a better recovery effect on AP than the traditional treatment method of ICD, but there are still practical obstacles such as poor light penetration and uneven distribution of photosensitive cells.140

The treatment of arrhythmias by local light stimulation has been demonstrated to be an effective strategy, but the global light stimulation of the heart is rare. In 2018, Uribe et al.141 used optogenetic technology to achieve global pacing of the heart in vitro, which effectively terminated arrhythmia. However, the energy required for global pacing is high, which will cause irreversible damage to cardiomyocytes and may cause other cardiac diseases.142 Crocini et al.143 proposed an all-optical platform that effectively addresses this issue by employing a multibarrier illumination mode. The results showed that in terms of the efficacy of arrhythmia recovery, the triple-barrier stimulation was equivalent to the whole ventricular stimulation, whereas only a quarter of the power used by the latter was required.143

Advanced soft-biological interfaces are crucial for the clinical translation of optogenetic technologies to treat arrhythmias.144^,145 Lin et al.146 employed graphene electronic tattoos (GETs) technology and incorporated two layers of ultrathin elastomers onto the graphene substrate, thereby fabricating a biological interface applicable to the heart in vivo [Fig. 8(a)]. In a mouse heart model, the GET-electrodes exhibited a lower signal-to-noise ratio in comparison to traditional electrodes and successfully accomplished cardiac pacing [Figs. 8(b) and 8(c)]. GET-electrodes were incorporated into mouse hearts that expressed the photoactivated opsin ChR2. This integration realized the light stimulation of the heart, concurrent with simultaneous electrophysiological sensing. Upon light stimulation, the heart was efficiently stimulated and paced, and normal electrocardiogram signals were recorded without any substantial light-induced artifacts. In a rat model of atrioventricular block (AV block), the application of GET-electrodes successfully reestablished the ventricular rhythm without perturbing heart contraction within a brief period [Fig. 8(c)]. The fabricated graphene biointerface exhibits remarkable electrochemical performance and can be utilized for the treatment of arrhythmia in mice with good stability. This work paves the way for the forthcoming development of cardiac biointerfaces in large mammals.

Neurological diseases may disrupt the neural pathway between the central nervous system and muscles, thereby causing motor dysfunctions in patients.147 Herrera-Arcos et al.148 conducted a study that functional optogenetic stimulation (FOS) and functional electrical stimulation (FES) were applied to treat muscle rehabilitation. Following the administration of general anesthesia to transgenic mice expressing ChR2, the tibial nerve of the mice was stimulated by FOS or FES to record the force and electromyography of the lateral fibularis muscle [Figs. 9(a) and 9(b)]. The FOS curve exhibits a significant decay after reaching its peak, ultimately stabilizing at a steady state. By contrast, the attenuation of the FES curve following its peak is markedly less pronounced than that of the FOS curve, making it attain steady state more rapidly at a higher level [Fig. 9(c)]. This result suggests that FOS provides a more accurate and reproducible means of muscle regulation, providing a theoretical basis for future bio-robotics research and development.

The clinical translation of optogenetics is constrained by limited light tissue penetration and the requirement for invasive interventions.149 To solve this problem, Hong et al.150 developed an ultrasound-mediated deep-tissue optogenetic illumination technology. This approach employs Ag/Co co-doped ZnS nanoparticles as mechanoluminescent materials, which are systemically delivered to deep brain tissues via blood circulation [Fig. 10(a)]. Following surface charging with 400 nm light, focused ultrasound (FUS) triggers the release of 470 nm blue light to activate ChR2-expressing neurons [Fig. 10(b)]. In mice models, this method enabled noncraniotomy modulation of hindlimb movement with an FUS-triggered light intensity of ∼1mW·mm−2, a focal volume of ∼700μm, and a response latency of 10 ms [Figs. 10(c) and 10(d)].150 This study provides a novel pathway for noninvasive optogenetic neural regulation.

Enteric neuropathy is considered one of the causes of functional gastrointestinal disease disorders.151^,152 Hotta et al.153 transplanted the enteric nervous system isolated from Wnt1-ChR2 mice into the colon of mice lacking neuronal nitric oxide synthase. Light stimulation induced the contraction of colonic smooth muscle and improved colonic motor function, indicating that there was a functional connection between the transplanted cells and the smooth muscle cells.153 The integration of optogenetic technology with other technologies (e.g., pharmacology154^,155 and biosensors156^,157) enables the construction of more precise models of intestinal neurological diseases and facilitates the achievement of precise interventions in intestinal function, holding the potential to develop novel therapeutic approaches.

Cancer is a disease caused by abnormal proliferation of cells, which can disrupt the function of organs and potentially spread to other parts of the body.158 Currently, the treatment of cancer is still a major challenge in the field of medicine.159 In 2016, Chernet et al.160 first conducted cancer research in Xenopus embryos using optogenetic technology. They found that regulating the electrical signals of frog tumor cells could significantly reduce the incidence of tumor formation and increase the frequency of tumor recovery to normal tissue.160 Subsequently, there has been a gradual increase in cancer research using optogenetic techniques. In 2021, He et al.161 introduced a new optogenetic tool called LiPOP [Fig. 11(a)]. To address the limitations of blue light penetration and reduce phototoxicity, LiPOP1 (containing specific mutations) was combined with UCNPs to enable wireless optogenetic control in living animals [Fig. 11(b)]. The tumor volume of mice in the experimental group was significantly smaller than that of mice in the control group after 1 month of light treatment [Fig. 11(c)]. The emergence of LiPOP tools is anticipated to achieve breakthroughs in the research and treatment of cancer by means of optogenetic technology. In another study, far-red light-controlled immunomodulatory engineered cells (FLICs) were combined with hydrogels for cancer postoperative immunotherapy [Fig. 11(d)]. Implantable hydrogel has the advantages of high conductivity and biocompatibility, which can effectively reduce inflammatory reactions.163 Upon implantation at the melanoma resection site in mice, these could reversibly modulate the release of cytokines following stimulation by red light [Fig. 11(e)].164 Post-treatment, the survival rate of mice subsequent to tumor resection approached 100% [Fig. 11(f)].162 Overall, the prominent feature of noninvasive optogenetic technology in cancer treatment is to eliminate tumor cells by modulating the immune response within the organism.

From a dialectical perspective, the presence of photosensitive proteins that activate nerve impulses indicates the existence of photosensitive proteins in nature that can inhibit nerve impulses. NpHR, derived from Natronomonas pharaonis, has been demonstrated to hyperpolarize the neurons under the irradiation of yellow light. Two improved versions of eNpHR2.026 and eNpHR3.055 are developed to enhance mammalian neuronal cell membrane targeting. In addition, the outwardly directed proton pump Arch from Halorubrum sodomense,21 ArchT from the Salmonella strain TP009,165 eBR from Halorubrum sodomense,40 and Mac from the spotted Leptosphaeria maculans21 have all been demonstrated to possess the capacity to inhibit neuronal activity.

Optogenetic technology mediated by inhibitory photosensitive proteins has been widely applied in the biomedical field. The target diseases include central nervous system diseases, circulation system diseases, and urinary system diseases. The pathogenesis of central nervous system diseases is complex, involving the interaction of genetic, environmental, and immune factors.166^–168 Inhibiting neuronal impulses may also have a positive effect on diseases.

The dentate gyrus is the entrance to the hippocampus, composed of excitatory granule neurons and inhibitory GABAergic interneurons.169 It has been clearly established that the imbalance between these two types of neurons is related to the pathogenesis of Alzheimer’s disease (AD).170^,171 Within the hippocampal circuitry, hilar interneurons are known to modulate this delicate balance.172 To investigate the function of hilar GABAergic interneurons in AD, Andrews-Zwilling et al.173 expressed eNpHR3.0 in hilar GABAergic interneurons in AD mice. After exposure to yellow light, the spatial memory and learning capacity of mice were impaired, whereas their motor coordination and exploratory activities remained unaffected.173 The results demonstrated that hilar GABAergic interneurons play a pivotal role in the control of learning and memory, thereby establishing the basis for the exploration of diverse neuronal functions by means of optogenetic technology in the future.

The pathological feature of Parkinson’s disease (PD) is the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), which affects the activity of the subthalamic nucleus (STN).174^,175 Deep brain stimulation of STN is an effective treatment for PD,113^,176 but the target cell types and the mechanisms are unknown. In 2009, Gradinaru et al.175 used optogenetic technology to systematically study different components of the PD neural circuit. They believed that the direct frequency-dependent effect on afferents to the STN region was the main direct target of DBS therapy for PD.175 On the basis of Gradinaru et al.’s research, Xie et al.177 further investigated the STN using optogenetic techniques and further verified that the pathological mechanisms of PD include dopamine deficiency and STN hyperactivity, emphasizing the important role of the STN in the treatment of PD.177 Clinical studies have found anatomical connections between the zona incerta (ZI) and STN, and its GABAergic neurons may affect the activity of STN.178 In addition, ZI GABAergic neurons may compensate for dopamine deficiency to some extent, indicating that ZI may be a complementary target for PD.179 Based on this study, Chen et al.180 investigated the GABAergic neurons of ZI using chemical genetics and optogenetic methods, and the results demonstrated the role of GABAergic neurons of ZI in the motor symptoms of PD.

In the process of exploring new avenues for PD treatment, the method of transplanting nerve cells has gradually gained attention. Studies have shown that transplanting neurons differentiated from human pluripotent stem cells can assist the recovery of neurological diseases.181^,182 To investigate its mechanism, Steinbeck et al.183 used optogenetic technology to real-time regulate mesencephalic dopaminergic (mesDA) neurons derived from human embryonic stem cells. The results demonstrated the critical role of transplanted neuron activity and connectivity in behavioral recovery, providing a framework for subsequent research and treatment strategy optimization [Fig. 12(a)].183

Seizures of epilepsy are the result of excessive synchronization of neurons.118 Therefore, researchers are exploring the application of optogenetic technology for neural hyperpolarization to enhance the management of epilepsy symptoms. The hypocretin/orexin neurons (HONs) in the lateral hypothalamus have a controlling effect on the electrical excitation of the brain, and their abnormal activity may be related to epileptic seizures.185^,186 Li et al.184 conducted experiments using a mouse model of epilepsy and discovered that the activity of HONs prior to seizures is correlated with seizure intensity and may exacerbate seizure episodes. Furthermore, lateral hypothalamic DBS (LH-DBS) has been shown to inhibit the activity of these HONs, effectively reducing the frequency and severity of seizures [Fig. 12(b)].184 This finding presents a novel potential strategy for the treatment of epilepsy. Similarly, Berglind et al.187 attempted to express NpHR3.0 in pyramidal neurons in the hippocampus of mice, and the experiments showed that light stimulation of pyramidal neurons could inhibit epileptic-like outbursts.187

Mesial TLE usually entails the surgical excision of the anterior hippocampus and amygdala.188 However, a subset of patients may still encounter seizure recurrence after the operation, suggesting the potential existence of lesions in other regions. Jamiolkowski et al.42 proposed that fasciola cinereum (FC) may be a promising target for epilepsy treatment. First, two-photon calcium imaging of FC neurons was performed on Cre transgenic mice. The results demonstrated that FC neuronal calcium activity was consistent with epileptic spiking activity. This suggests that the FC region where neurons are located is highly active at the onset of TLE. Subsequently, an optogenetic approach was employed to transduce the inhibitory photosensitive protein soma-targeted Guillardia theta anion-conducting channelrhodopsin 2 (stGtACR2) into the neurons of mouse FC. In the absence of light, the FC neurons of epileptic mice exhibited high levels of activity. Following light stimulation, the activity of the FC neurons was inhibited, resulting in a reduction in epileptic symptoms. This result suggested that the FC is a reliable target for the treatment of epilepsy in mice. Given that the mouse hippocampal structure differs from that of humans,189^,190 to further ascertain the applicability of this conclusion to the treatment of human epilepsy, Jamiolkowski et al. performed stereoscopic electroencephalography (sEEG) implantation on six epilepsy patients. Subsequently, in patients with recurrent epilepsy after laser interstitial heat therapy, the root cause of seizures was identified as FC through sEEG localization. After further laser ablation of FC, the patient’s seizure frequency decreased by 83%, indicating that FC is a targeted therapeutic source for human epilepsy recurrence [Fig. 12(c)]. This study includes animal experiments and human research findings, manifesting the reliability of the conclusions and presenting a direction for the future clinical treatment of TLE.

The main characteristic of psychiatric disorders is impaired social interaction.191^,192 Previous studies have demonstrated that the ventral hippocampus (vHPC), a region downstream of the basolateral amygdala (BLA), is associated with social interactions in rodents.193^,194 To explore the regulatory function of neural pathways between BLA and vHPC in relation to social behavior in rodents, Felix-Ortiz et al.195 employed optogenetics to conduct bidirectional modulation of BLA neurons in mice. Initially, inhibitory photosensitive proteins were utilized to regulate the activity of BLA neurons. It was observed that light stimulation resulted in an augmentation of social interaction in the experimental group of mice. Subsequently, upon switching to excitatory photosensitive proteins, the outcomes of light stimulation were contrary to those aforementioned [Figs. 13(a) and 13(b)]. The aforementioned experimental results suggest that the projection from the BLA to the vHPC plays a vital role in social behavior, thereby presenting a new direction for the treatment of psychiatric disorders by optogenetic technology.

Chronic kidney disease (CKD) and heart failure (HF) have a high prevalence and exacerbate each other, but the mechanism of heart–kidney interactions and the role of renal afferent nerves are unknown.196 To further elucidate the link mechanism between them, Cao et al.53 employed optogenetics and viral tracing to regulate the subfornical organ (SFO)—paraventricular nucleus (PVN)—rostral ventrolateral medulla (RVLM) pathway [Fig. 13(c)]. In the mice models of CKD and HF, the SFO-PVN-RVLM pathway is activated. However, when this pathway is inhibited by light stimulation, the discharge of the related neurons is decreased, and the organ function is improved.53 This study demonstrates the positive role of the SFO-PVN-RVLM pathway in the treatment of CKD and HF.

It is difficult for electrical stimulation to achieve cardiac restitution through local excitation or inhibition, but it could be achieved using different types of photosensitive proteins.14 Currently, a considerable number of studies focused on modulating heart activity through the inhibition of the impulses of myocardial cells.197^–199 Yu et al.51 investigated the impact of optogenetic technology on ventricular arrhythmia by expressing ArchT in the left stellate ganglion (LSG) neurons of beagle dogs. Upon light stimulation, it was observed that the function of LSG was remarkably inhibited, and ventricular arrhythmias (VAs) were successfully suppressed as well. In another study on VAs, Funken et al.200 introduced ArchT into cardiomyocytes and induced VAs in Langendorff-perfused mouse hearts through electrical stimulation. The results suggested that the termination rate of VAs was significantly higher than that of the control group.

The traditional optogenetic technology, with its wired power supply and high invasiveness, poses obstacles to its research and further clinical translation in the field of cardiac neural regulation.201^–204 Although wireless optical genetic technology has made progress, energy issues have limited its development. Zhou et al.205 introduced a wireless self-powered optogenetic modulation system, which addresses the energy supply issue. This system comprises a triboelectric nanogenerator and LED photoelectrodes, capable of converting the biomechanical energy of body movement into electrical energy [Fig. 14(a)]. Subsequently, researchers induced ArchT protein expression in LSG neurons of experimental dogs through the injection of virus. After long-term optogenetic therapy, the expression of c-fos and NGF decreased, indicating that optogenetic technology inhibits the remodeling of LSG neurons after myocardial infarction (MI) [Fig. 14(b)]. According to the neural records of different groups of dogs, MI significantly increases the frequency and amplitude of LSG neural activity, but this activity is significantly inhibited after regular optogenetic therapy [Fig. 14(c)]. The wireless self-powered optogenetic modulation system has the potential to meet the optical lighting requirements for optogenetic neural regulation, thereby facilitating the development of long-term optogenetic therapy equipment.

Retinal degenerative diseases are typical cases of optic nerve system diseases. The classic pathological feature is the irreversible damage to retinal photoreceptor cells, which is one of the causes of blindness.206^,207 The excitatory photosensitive proteins can stimulate nerve impulses upon light stimulation, which offers a possibility to be used to treat blindness.25^,26 As early as 2006, Pan et al.210 first applied optogenetics to the study of degenerative retinal diseases and demonstrated that this strategy is feasible for visual recovery in certain stages of degenerative retinal diseases.208 However, the targeted expression of ChR2 remains an urgent issue to be addressed. Shortly thereafter, a methodology exploiting tyrosine mutations within AAV vectors to achieve targeted ChR2 expression in ON bipolar cells was devised, enhancing signal amplification and photon capture, with preliminary evaluations confirming its safety.209 For instance, the identification of suitable AAV viruses and promoters for human use, as well as the development of appropriate light pulse devices, is among the pressing issues that demand immediate resolution. A multitude of research teams have dedicated their efforts to optimizing optogenetic tools. Pan et al.210 and Wyk et al.211 have respectively proposed and constructed L132 and T159 site mutants of ChR2 and Opto-mGluR6. These two tools displayed remarkable performance in terms of photosensitivity and physiological compatibility. With the continuous improvement of technology, optogenetic technology has been successfully applied from rodents to live primates, promoting the translation of optogenetic technology to clinical applications.212

In 2021, optogenetic technology was applied in the treatment of a patient with retinitis pigmentosa (RP) for the first time. The researchers injected GS030-DP into the patient’s eye and successfully expressed the sensitive channel protein ChrimsonR-tdTomato in retinal ganglion cells (RGCs), where as wearing GS030-MD goggles to achieve light stimulation of the retina at the corresponding intensity [Fig. 15(a)]. Following the administration of the standard course of treatment, the patient’s perception, positioning, and other functions were restored. In conjunction with electroencephalogram (EEG) recordings, optogenetic stimulation of the retina can be effectively conveyed to the primary visual cortex, thereby regulating its activity and contributing to the restoration of visual function [Figs. 15(b) and 15(c)].19 The research of optogenetic technology in the context of degenerative retinal diseases has reached a relatively advanced and sophisticated stage.

In optogenetic therapy for RP, activating photosensitive proteins necessitates light sources with intensities exceeding ambient levels, typically requiring optical amplifiers.213 Current optical amplifier systems suffer from bulkiness, low energy efficiency, and difficult integration. Organic light-emitting diodes (OLEDs) emerge as promising compact micro display light sources. Hillebrandt et al.214 developed specific OLEDs for optogenetic therapy of vision loss [Fig. 16(a)]. The device was constructed via sequential deposition of an Ag anode, MoO3 interface layer, p-type doped hole transport layer (Spiro-TTB:F6TNAP), NPB electron blocking layer, emission layer [NPB:Ir(MDQ)2acac], BAlq hole blocking layer, n-type doped electron transport layer (BPhen:Cs), semi-transparent Ag cathode, and NPB coating layer on a silicon substrate [Fig. 16(b)]. By optimizing the microcavity structure to match the emission wavelength with the absorption spectrum of ChrimsonR (600 nm), the device achieved a photon flux of 3×1016photons/(cm2·s) within a ±10deg emission cone, satisfying the optogenetic stimulation requirements. At 10 V, the brightness of a single stacked OLED reaches 368,000cd/m2, but there is an efficiency roll off problem at high brightness.214 Hillebrandt et al.214 subsequently developed a tandem-stacked architecture to enhance the efficiency and stability of single-stack OLEDs. This design incorporates a charge generation layer (a 10 nm-thick interface layer of MoO3 and Spiro-TTB:F6TNAP) to connect two luminescent units in series, enabling a single electron to excite two photons and thereby doubling the quantum efficiency [Fig. 16(c)]. The tandem-stack OLEDs achieved a peak brightness of 1,152,000cd/m2, with the current density reduced by ∼50% under identical photon flux, significantly mitigating heat loss. The half-brightness lifetime of the 0.5mm×0.5mm tandem-stack device was extended to 800 h through optimization of heat dissipation and pulse driving [Fig. 16(d)].214 These results suggest that OLEDs are able to meet the requirements of high-brightness and directional emission for optogenetic therapy through structural optimization. The tandem-stack technology notably improves both efficiency and operational lifespan, offering a viable solution for next-generation micro display light sources in optical amplification prostheses. To achieve high-resolution control of retinal cells and better biosafety, optogenetic devices are gradually developing toward miniaturization, wireless, and green environmental protection.141^,211^,212 These technologies, rooted in the advancement of miniaturized optoelectronic devices within biophotonics, furnish critical hardware support for the clinical translation of optogenetics.215

Besides the excitatory photosensitive protein, the inhibitory photosensitive protein, eNpHR, has also been applied in the research of visual restoration. Busskamp et al.216 believed that downstream cells of the retina, such as bipolar cells and ganglion cells, have strong signal adaptation and integration abilities. These cells can reencode and interpret hyperpolarized signals, converting them into effective visual signals. Therefore, they expressed eNpHR in a mouse model and restored visual behavior in retinal pigment degeneration mice.216 More importantly, the feasibility of this method was demonstrated in human ex vivo retinal cultures.216

At present, several clinical trials of optogenetic therapy for RP are underway (NCT02556736, NCT04919473, and NCT04945772).217^,218 However, there are some challenges before this technology can be truly applied in clinic, such as the risk of the excitation light of photosensitive proteins exceeding the safe threshold of the retina,219 ethical issues with the use of viral vectors, immunogenicity,220^,221 and the current regulatory framework may lack joint evaluation criteria for optogenetics gene delivery systems.222 The immunogenicity and long-term safety data of AAV vectors must comply with regulatory requirements for gene therapy, whereas the safety evaluation of light stimulation devices involves medical device approval processes, thereby presenting significant challenges for cross-disciplinary coordination. Finally, there are significant differences in the number and degree of remodeling of residual retinal cells among patients with retinal degeneration, making it difficult to establish uniform inclusion criteria.217^,223 Therefore, the clinical translation of optogenetic technology for vision recovery still requires continued efforts from multiple fields.

As ChR2 was successfully applied to control neuronal activity in mammalian cells, optogenetic technology has been increasingly applied in the biomedical field in the past 20 years. In this review, we summarized the recent progress of optogenetic technology in biomedical applications through two categories: to activate or inhibit neurons. Most of the studies are basic research that intends to figure out the pathogenesis or treat the diseases distributed in various organs (Table 2). Currently, the progress and breakthroughs of optogenetic technology have been achieved in larger animals such as New Zealand rabbits and beagle dogs.51^,241 Several clinical trials of optogenetic technology for retinal degeneration206^,242 and pain243 are undergoing. With the help of optogenetic technology, a patient with advanced retinitis pigmentosa has partially restored his vision.24 However, the translation of optogenetics to clinical applications still faces challenges.

The prerequisite of optogenetic technology applications is to express photosensitive proteins in target tissues. For the basic studies, viral transfection technology and transgenic animals can satisfy this condition. Viral vectors enable efficient gene delivery to specific neuronal populations, such as using CaMKIIα or GAD67 promoters for cell-type-specific expression.180^,244 However, applying these methods to clinical research remains challenging. The human immune system, evolved over millennia, poses significant barriers. Viral capsid proteins can trigger adaptive immune responses, leading to antibody-mediated clearance of transduced cells. Even though the photosensitive proteins are able to be successfully expressed in the human body, the long-term safety of photosensitive proteins should be carefully evaluated. Microbial-derived photosensitive proteins may induce chronic immune reactions, and their prolonged activation could disrupt neuronal physiology, potentially leading to neurodegeneration or functional deficits.206^,245 Preclinical studies in nonhuman primates have shown that humanized opsin variants reduce immunogenicity, but long-term safety evaluation data are still lacking.246^–248

Beyond technical hurdles, science ethics presents enormous challenges. Optogenetic interventions involve permanent genetic modification of organs such as the human brain. This practice raises questions about informed consent, particularly the irreversible nature of gene editing. Manipulating memory engrams or emotional states via optogenetics may potentially infringe on personal identity or free will. Regulatory frameworks for combined products (viral vectors and implantable devices) remain unclear. The social impact also involves equity issues: access to advanced optogenetic treatments may worsen healthcare inequalities. Furthermore, the applications of optogenetic technology in military or law enforcement fields have raised concerns about nontherapeutic neural manipulation. These challenges highlight the necessity of interdisciplinary collaboration among scientists, ethicists, and policymakers to ensure responsible research and applications.

Photosensitive proteins are mostly excited by blue light (470 nm) or yellow-green light (589 nm). However, the penetration depth of light in this band is lower than 5 mm, which is only applied to treat superficial lesions. How to deliver the light to the target organs (brain, heart, kidney, etc.) is a challenge of optogenetic technology. Although upconverting NPs or two-photon technology can improve the depth of light to a certain extent, it still does not make light pass through the skull or thoracic cavity. The implantation of optical fibers or wireless light sources may result in unexpected effects on target organs, such as tissue scars and thermal damage. Moreover, the complex microenvironment within tissues and the structural interference from optical fibers may induce light deflection, resulting in off-target activation. Therefore, to develop the specific light source devices that can be integrated into the body according to the target disease is the second challenge of optogenetic technology clinical applications. Nowadays, optogenetics and biophotonics have increasingly converged. The biophotonics provides critical technological supports (e.g., optical imaging, deep-tissue light delivery) for optogenetic manipulation, whereas the optogenetics drives innovations in biophotonic tools (e.g., miniaturized light sources, adaptive optics) to enable precise neuroregulation.

Optogenetic technology is a promising strategy to treat diseases through the activation of neural activity or the inhibition of neural activity according to the different pathogeneses. However, for some neurodegenerative diseases, including AD, PD, and IS, their pathogenesis is complicated and not fully understood, as it involves multiple areas of brain dysfunction. This area has low neural activity, but another area may have high neural activity. That is why different studies applied two opposite photosensitive proteins to the same disease, and the results suggested that both of them can alleviate the symptoms of the disease. Therefore, the complicated pathogenesis is another challenge for optogenetic technology clinical applications. Discovering the mechanisms of diseases can significantly enhance the applications of optogenetic technology.

Artificial intelligence (AI) refers to computer systems capable of performing tasks that historically required human intelligence and has become a transformative force across numerous fields. The integration of AI and optogenetics is leading to significant advancements in neuroscience and its related disciplines.249^,250 AI is expected to play a crucial role in the precise control of the expression and localization of photosensitive proteins, developing specific optogenetic treatment plans for individual genetic profiles, physiological characteristics, and other relevant data. In treating neurodegenerative diseases such as PD and AD, AI can analyze neuronal abnormalities within specific brain regions of patients and make accurate adjustments to light stimulation parameters, including the wavelength, intensity, and frequency.251 Furthermore, AI’s robust data analysis capabilities, combined with optogenetic technology, will play a role in the investigation of the mechanisms within disease-related neural circuits.252 In addition, AI will be integrated with other emerging technologies, such as quantum computing and nanotechnology, to further advance the development of optogenetics.253 Combined with quantum computing, AI can process complex neural models and optogenetic data more efficiently, thereby providing robust support for theoretical research in neuroscience. In conjunction with nanotechnology, it is possible to develop more advanced nanoscale optogenetic tools that achieve higher precision in neuronal manipulation and detection. By utilizing AI to simulate the processes of optogenetic therapy, the efficacy and potential risks can be predicted. This approach offers a more reliable reference for clinical trials and improves the success rate of these trials, which facilitates the rapid application of optogenetic technology for patient benefit.

In summary, optogenetics is an interdisciplinary field composed of optics, genetics, biology, and medicine. Therefore, every step in the development of optogenetics technology requires a lot of effort from researchers in various fields. In the past 20 years, optogenetics technology has been successfully applied in many basic studies and a few clinical trials. Even with the above challenges, it will benefit more patients in the near future.

Hongyou Zhao received his PhD/MD in 2014 from Chinese People’s Liberation Army (PLA) Medical School. After postdoctoral training at Louisiana State University (LSU), he joined Beijing Institute of Technology in 2020, where he is currently an associate researcher in the School of Medical Technology. His main research interests include the development and preclinical evaluation of new photosensitive drugs and the mechanism and clinical translation of transcranial phototherapy.

Hui Yue received his MS degree in 2022 from Jiangnan University. He currently works at Liaocheng People’s Hospital, where his main research focuses on the fundamental and clinical studies of neurological diseases.

Wenxin Chou is a postgraduate student of Beijing Institute of Technology under the supervision of Prof. Hongyou Zhao. Her research project is to investigate the anti-tumor immune effect and mechanism of water-dependent reversible photoacids.

Shanlin Yang is currently pursuing her PhD in laser medicine at the Chinese People’s Liberation Army (PLA) Medical School. Her research interests include photodynamic therapy against multidrug-resistant bacteria and the experimental validation and mechanism study of the “layered-analysis photodynamic therapy” theory.

Yidi Liu received her MS and PhD in laser medicine from the Chinese PLA Medical School through an integrated master’s and doctoral program in 2022. Since then, she has been working at the Department of Laser Medicine, Chinese PLA General Hospital, focusing on photodynamic diagnosis and treatment.

Mianwang He is an associate chief physician and associate professor of Neurology Department, Chinese PLA General Hospital, Chinese PLA Medical School. His main research interests include non-invasive neuromodulation, neurostimulation, transcranial phototherapy on neurological disorders, including headache, stroke, Parkinson’s disease, dementia, and neuropsychiatric disorders.

Yunqi Li is an associate chief physician in the Department of Gastroenterology, the First Medical Center, Chinese PLA General Hospital. He received his master’s and PhD degrees from Chinese PLA Medical School in 2013 and 2020, respectively. He specializes in the endoscopic diagnosis and tomographic photodynamic therapy.

Jianfei Guo serves as the vice president of Liaocheng People’s Hospital, the president of the Brain Hospital, and chief physician of the Department of Endocrinology. His main research focuses on the diagnosis and treatment of diabetic foot and various chronic wounds.

Haixia Qiu received her MD degree in 2006 from Chinese People’s Liberation Army (PLA) Medical School. She is currently the director of the First Medical Center Laser Medicine Department, deputy chief physician, graduate supervisor, and postdoctoral cooperative supervisor. Her main research direction is the clinical application and mechanism study of laser technology in benign and malignant diseases.

Yilei Xiao received his PhD/MD degree in 2016 from Shandong University. After completing his postdoctoral research at Shanghai Jiao Tong University from 2017 to 2019, he is currently the chief expert of neurosurgery and vice president of the Brain Hospital at Liaocheng People’s Hospital. His main research interests focus on the fundamental and clinical studies of neurological diseases.

Ying Gu, an academician of the Chinese Academy of Sciences. Currently, she is the chief physician of the Department of Laser Medicine, Chinese PLA General Hospital, and a professor of Chinese PLA Medical School. Her research interests include the photodynamic therapy for port wine stains, tomographic photodynamic therapy, development and clinical evaluation of new photosensitive drugs, developing various laser devices for disease diagnosis and therapy.