Neuron

Received: 12 February 2023
DOI: 10.1002/bmm2.12023
REVIEW
- Accepted: 16 April 2023
Advanced near‐infrared light approaches for

neuroimaging and neuromodulation
Hongqiang Yin1 | Wuqiao Jiang1,2 | Yongyang Liu1,2 | Dongyang Zhang1,2 |

Feng Wu1,2 | Yejun Zhang1 | Chunyan Li1,2 | Guangcun Chen1,2 |
Qiangbin Wang1,2,3
1
CAS Key Laboratory of Nano‐Bio Interface, Suzhou Key Laboratory of Functional Molecular Imaging Technology, Division of Nanobiomedicine and i‐
Lab, Suzhou Institute of Nano‐Tech and Nano‐Bionics, Chinese Academy of Sciences, Suzhou, China
2
School of Nano‐Tech and Nano‐Bionics, University of Science and Technology of China, Hefei, China
3
College of Materials Sciences and Opto‐Electronic Technology, University of Chinese Academy of Sciences, Beijing, China
Correspondence
Guangcun Chen and Qiangbin Wang, Abstract
Suzhou Institute of Nano‐Tech and Almost all physiological processes of animals are controlled by the brain,
Nano‐Bionics, Chinese Academy of
including language, cognitive, memory, learning, emotion and so forth. Minor
Sciences, Suzhou 215123, China.
Email: gcchen2011@sinano.ac.cn and brain dysfunction usually leads to brain diseases and disorders. Therefore, it' is
qbwang2008@sinano.ac.cn greatly meaningful and urgent for scientists to have a better understanding of
brain structure and function. Optical approaches can provide powerful tools
Funding information
National Natural Science Foundation of for imaging and modulating physiological processes of the brain. In particular,
China, Grant/Award Numbers: 22127808, optical approaches in the near‐infrared (NIR) window (700–1700 nm) exhibit
22177128, 22204172, 21934007, 22174158;
the National Key Research and
excellent prosperities of deep tissue penetration and low tissue scattering and
Development Program, Grant/Award absorption compared with those of visible windows (400–700 nm), which
Number: 2021YFF0701804; the Science provides a promising approach for scientists to develop desired methods of
and Technology Project of Suzhou, Grant/
Award Numbers: SZS201904, SJC2021001; neuroimaging and neuromodulation in deep brain tissues. In this review,
the Natural Science Foundation of Jiangsu variable types of NIR light approaches for imaging and modulating neural
Province, Grant/Award Numbers:
ions, membrane potential, neurotransmitters, and other critical molecules for
BK20222016, BE2022753, BE2022745;
Chinese Academy of Sciences, Grant/ brain functions and diseases are summarized. In particular, the latest break-
Award Numbers: YJKYYQ20200036, through research of brain imaging and brain regulation in the NIR‐II window
121E32KYSB20180021, ZDBS‐LY‐SLH021
(1000–1700 nm) are highlighted. Finally, we conclude the challenges and
prospects of NIR light‐based neuroimaging and neuromodulation for both
basic brain research and further clinical translation.
KEYWORDS
nanoprobes, near‐infrared light, neural ion channels, neuroimaging, neuromodulation
-
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1 | INTRODUCTION the programmed change of Na+/K+ channel activity to

input Na+ or output K+ generates and transmits action
The brain is the most sophisticated and important organ potentials, which can propagate along the axon to the
of the body, which controls almost all abilities of humans synaptic end with a millisecond temporal resolution.
and animals for survival in the surrounding environment, Finally, the action potentials drive the synapse to release
including cognitive, memory, learning, emotion, action, neurotransmitters (such as glutamate, dopamine, acetyl-
temperature homeostasis and so forth.[1,2] The brain choline according to the type of neurons) to activate the
works as a highly complex electrochemical computing next cell. Such electrochemical processes in neural cells
machine, which realizes its functions through the neural enable multicellular interactions, thus generating neural
network formed by the huge number of neural cells networks and brain functions. Its disorder can also cause
(mainly the neurons) and their interconnections. For the serious brain diseases. The fully understanding of the
human brain, it was estimated that the brain is composed mechanisms of brain information processing and brain
of 8.6 � 1010 cells and more than 1 � 1015 synaptic diseases relies on the neuroimaging and neuro-
connections.[3] In this system, electrical signals (mem- modulation techniques that can high‐fidelity monitor and
brane potentials) and chemical signals (neurotransmit- modulate multiple neural signals of the brain in vivo,
ters) are the main ways for neurons to encode, process including the neural signaling ions, membrane poten-
and transmit information (Figure 1). Generally, neurons tials, neurotransmitters, as well as brain disease‐related
accept information at the dendritic end of the cell body physiological and pathological molecules, which remain
via neurotransmitters and various ion channels. Then, great challenging.
F I G U R E 1 Schematic of the basic signaling mechanism in the brain. The mammalian brain comprises more than billions of neurons,
and its functions are dependent on the basic signaling and multidimensional interactions between these neurons. Ion channels in the cell
membrane can respond to extracellular signals and control the input or output of different ions (such as Na+, K+, Ca2+, and Cl−), thus
inputting and generating neural signals (1). Electrical signaling is the basic form of information encoding, processing and transmission in
neurons, which is generally driven by the programmed change of Na+/K+ channel activity and the subsequent membrane voltage wave (2).
Neurons output information to other neural cells via synaptic chemical signals (such as glutamate, dopamine, acetylcholine
neurotransmitters), which is the basic form of communication between individual neural cells in the mammalian brain (3).
Electrochemical computing of neural cells is the basis of brain function, and its disorder can also cause serious brain diseases (4).
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Nowadays, numerous neuroimaging and neuro- fluorescence imaging is limited due to poor tissue pene-
modulation methods across many spatial and temporal tration depth (<1 mm) of visible light (Figure 2).[16,17]
scales have been developed to explore the brain func- Therefore, in vivo imaging with visible light compromised
tions. As early as the late 18th century, electrode‐related the spatiotemporal resolution once deep tissue imaging is
technologies have been successfully used to monitor performed because of strong tissue absorption and sig-
and regulate neural electrical activity in a flog by an nificant tissue autofluorescence (Figure 2a,b).[14,18,19] The
Italian scientist. At present, electrode‐based technologies, NIR window (700–1700 nm) exhibits deep tissue pene-
including various microelectrodes and electro‐ tration and low scattering and tissue autofluorescence
encephalography (EEG), have been able to monitor and compared with that of visible window (Figure 2c,d),[15]
regulate the electrical activity of the brain at the single which provided a promising strategy for brain imaging
cell or the whole brain scales, and have been widely used with noninvasive and reached a high spatiotemporal
in basic research and clinical practice.[4] However, EEG is resolution of sub‐cellular 10 μm resolution.[17,20,21] In
limited by its spatial resolution, accuracy and sensi- particular, the cutting‐edge optical approach using the
tivity.[5] While microelectrode technology mostly requires light in the second NIR window (NIR‐II, 1000−1700 nm)
invasive implantation in vivo and can only monitor a has shown a penetration depth of more than 1 cm both in
limited number of local neurons without cell speci- in vivo imaging and modulation, which opens new ca-
ficity.[6] Currently, magnetic field‐ and ultrasound‐based pabilities for the optical approach to achieve precise op-
non‐invasive techniques have also been developed to tical imaging and manipulation of cell functions in
study the structure and functions of the brain.[7–9] vivo.[15,17,21,22]
However, magnetic imaging and modulation techniques In this review, we provide an up‐to‐date summary of
only possess a millimeter cubic spatial resolution and the recent NIR light‐based neuroimaging and neuro-
second‐level temporal resolution, which can't fully meet modulation approaches, including the novel imaging
the need to monitor high‐speed neural activity.[10] The techniques for neural signaling ion, neuronal membrane
ultrasound method was limited by the poor tissue tar- potential, neurotransmitters and neuromodulators, cere-
geting and possible metastatic dissemination.[11] More bral vasculatures, neuropathological detection and NIR
importantly, none of these techniques can be used to fully light‐based strategy for neural electrical activity regula-
monitor or modulate the activity of extremely large tion and brain disease therapy. In particular, we highlight
numbers of neural cells and their connections in the the latest breakthrough research in brain imaging and
brain at single‐cell resolution. brain regulation in the NIR‐II region. Moreover, the
Optical approaches have emerged as a promising challenges and prospects for NIR light‐based neuro-
strategy for high‐fidelity and high‐throughput brain im- imaging and neuromodulation techniques are discussed.
aging and modulation studies due to their numerous
intrinsic advantages.[12,13] First, optical strategies are
generally noninvasiveness and safe, which can realize 2 | THE APPLICATION OF
remote and non‐contact brain imaging and regulation. NEUROIMAGING IN NIR WINDOWS
Second, optical approaches with micrometer‐level spatial
resolution and sub‐millisecond temporal resolution can Brain imaging techniques are promising approaches for
meet the need of real‐time monitoring and modulation at scientists to visibly understand the functions and struc-
a single cell level. Third, optical approaches are easy to tures of the brain directly.[23] Therefore, developing brain
operate and can zoom in or zoom out to a single‐cell scale imaging techniques with noninvasive and high spatio-
or the whole brain scale. Also, it can be convenient to temporal resolution is an urgent need for basic and
adjust the light wavelength, intensity, and frequency to clinical research.[12] To date, a series of optical imaging
meet the needs of multi‐channel research. Fourth, optical approaches have been developed to explore the structure
strategy enables the study of different subpopulations of and functions of the brain. The first optical approach for
neurons via light focus in combination with the specif- monitoring neuronal activity was developed by the Hill
ically expressing reporter genes or light‐sensitive proteins and Keynes in 1949.[24,25] With the discovery of fluores-
in specific neuronal subpopulations. cent proteins, the development of optical neuroimaging
So far, a large number of brain imaging contrast agents technology has been greatly promoted. More recently, the
have been developed for brain imaging and modulation advancement of the NIR optical method (700–1700 nm)
both in the visible (400–700 nm) and near‐infrared (700– greatly reduced the absorption and scattering effects of
1700 nm) windows.[14] The contrast agents with visible light in living tissues, making it possible to study the
light emission showed good properties of in vitro fluo- neural activity in living brains with high spatiotemporal
rescence imaging, while the application of in vivo resolution.[12] Nowadays, large variable kinds of NIR
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F I G U R E 2 Wavelength‐dependent interaction between light and the brain. (a) Schematic of scattering and absorption of light in
the tissue during in vivo imaging. (b) Reduced scattering and absorption of light with the increase in wavelength in the 400–1700 nm region.
(a, b) Reproduced with permission.[14] Copyright 2021, Springer Nature Singapore Pvt Ltd. (c) The effective penetration depth of light with
different wavelength in the brain. (d) The percentage of photons of light with different wavelength reaches a depth of 4 mm in the brain.
(c, d) Reproduced with permission.[15] Copyright 2022, Oxford University Press on behalf of China Science Publishing & Media Ltd.
techniques have been developed for brain imaging, in synaptic vesicles.[31] The induction of synaptic plas-
including neuronal membrane potential, ion concentra- ticity, closely associated with cognitive and memory, re-
tion, neurotransmitters and neuromodulators, cerebral lies on a transient rise in intracellular Ca2+ concentration
vasculatures, neuropathological detection, and so forth. through post‐synapse.[32] Ca2+ also acts as the second
message to activate calcium related signaling pathway
which regulate gene transcription.[33] Therefore, moni-
2.1 | Ion imaging in neurons using NIR toring Ca2+ fluctuation is particularly important in the
probes nervous system. Nowadays, a variety of Ca2+ indicators
have been developed for monitoring the intracellular
Ion plays an important role in regulating the electrical fluctuations of Ca2+, including bioluminescent Ca2+ in-
activity of neurons, including neuronal excitation and dicators, chemical (or synthetic) calcium indicators and
transmission.[26,27] Moreover, some kinds of ions (Ca2+, genetically encoded calcium indicators (GECIs).[34] Most
K+, Mg2+, etc.) also participate in various biological of the Ca2+ indicators exhibit the excitation and emission
processes, including neuronal proliferation, differentia- peak at the visible fluorescence windows. The classic
tion, regeneration and apoptosis.[28,29] Therefore, devel- bioluminescent of Ca2+ indicators were aequorin derived
oping optical imaging approaches for detecting the from the luminescent jellyfish aequorea Victoria.[35] When
spatiotemporal dynamics of ion fluctuations is greatly the aequorin, which contains three Ca2+‐binding sites,
valuable. captures Ca2+, it undergoes a conformational change,
Ca2+ is a central mediator to perform various intra- which induces coelenterazine oxidation to coelenter-
cellular signals, which control a large variety of functions amide accompanied by an emission at about 470 nm.[36]
in all types of neurons.[30] In the pre‐synapse, Ca2+ in- The representative of chemical calcium indicators, such
fluxes trigger the release of neurotransmitters containing as a series of fura, Oregon Green BAPTA and fluo
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indicators, consists of calcium chelator and fluorophore, pocket of biliverdin, which exhibited a negative fluores-
whose conformational changes result in the visible cence signal upon Ca2+ binding (Figure 3a,b). Among
emitted fluorescence upon Ca2+ captured.[37] NIR‐GECOs, NIR‐GECO2G exhibits more brightness and
The GECIs were developed using two mechanisms, dynamic range. However, the NIR‐GECOs lacked pho-
including single‐fluorophore ones and FRET. For single‐ tostability, which limits the maximum recording rate of
fluorophore GECIs, in 2019–2020, Qian et al. developed a calcium fluctuations.
series of NIR GECIs shared the same chromophore bili- The scaffold of FRET‐based GECIs consists of two
verdin (λex = 678 nm; λem = 704 nm), an NIR fluorescent FPs, which are linked by the calcium‐binding protein
protein (IFP).[38,39] The NIR‐GECOs were generated by calmodulin (CaM)‐M13 peptide pair or a troponin C
inserting calcium‐sensing module containing calmodulin domain. In 2021, Verkhusha et al. developed an NIR
and its binding peptide RS20 into the loop near the GECIs (iGECIs), which employed two optimized FPs,
F I G U R E 3 The NIR Ca2+ indicators. (a) Schematic diagram of NIR‐GECO1s and its mechanism of binding to Ca2+. The excitation and
emission spectra of NIR‐GECOs in the presence and absence of Ca2+. Dashed lines represent the excitation spectrum, and solid lines
represent the emission spectrum. (b) Traces of wide‐field imaging of Ca2+ with NIR‐GECO1s while neuronal activity is evoked. (a, b)
Reproduced with permission.[38] Copyright 2019, Nature Publishing Group. (c) General view of iGECI and its response to Ca2+. Spectrum
of iGECI in the absence (red line) and presence (black line) of Ca2+ measured in cell lysates of HEK293T cells. (d) Spontaneous Ca2+
monitoring with iGECI in cultured neurons. (c, d) Reproduced with permission.[40] Copyright 2021, Nature Publishing Group.
(e) Schematic of HaloCaMP and its mechanism of response to Ca2+. HaloCaMP1a contains CaM‐binding peptides from myosin light chain
kinase (MLCK), and HaloCaMP1b obtains CaM‐dependent kinase (CKK) to the N‐terminus. Spectrum of absorption (solid lines) and
emission (dashed lines) of HaloCaMP1a‐JF635 in the absence and presence of Ca2+. (f) Ca2+ imaging of HaloCaMP1a and 1b labeled with
different JF‐HTL to different numbers of APs. (e, f) Reproduced with permission.[41] Copyright 2021, Nature Publishing Group.
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miRFP670 (λex = 640 nm; λem = 670 nm) and miRFP720 of generating action potential and synaptic trans-
(λex = 670 nm; λem = 720 nm), as donor and acceptor.[40] mission.[49] Abnormal fluctuation of intracellular and
Two FPs were connected with a linker that consists of extracellular K+ is closely associated with the develop-
CaM and the CaM‐binding peptide M13. Ca2+ binding ment of brain diseases and disorders, such as epilepsy
induces the intramolecularly conformational changes, and degenerative diseases.[50] Hence, developing high
resulting in a decrease in the spatial distance between the spatiotemporal resolution of K+ sensors to monitor K+
two FPs (Figure 3c‐d). The iGECIs exhibit 5 folds higher fluctuation is extremely meaningful. Although several K+
brightness and 18‐fold more photostable than NIR‐ probes have been developed, such as genetically encoded
GECOs. potassium ion indicator (GEPII),[51] organic indicator
Interestingly, in 2021, Deo et al. developed two NIR TAC‐Red,[52] QD‐based K+ nanosensors,[53] etc., most of
hybrid Ca2+ indicators, HaloCaMP1a and HaloCaMP1b, them exhibit excitation and emission in visible light
which contain JF635‐HTL and an engineered circular windows and are not sensitive enough for detecting K+
permutant HaloTag (cpHaloTag). The C‐terminus of waves. Kobertz et al. described an NIR fluorescent K+
HaloCaMP is linked with CaM, and N‐terminus is fused sensor (KNIR‐1) with emission >650 nm which is able to
to CaM‐binding peptides from myosin light chain kinase detect fluctuation of intracellular and extracellular K+ (0–
(MLCK) or CaM‐dependent kinase (CKK) (Figure 3e).[41] 200 mM).[54] Liu et al. developed two highly sensitive
Upon Ca2+ binding, the HaloCaMP1a‐JF635 (λex = and selective K+ nanosensors, and both of them are
640 nm; λem = 653 nm), linked with MLCK peptide, involved in the K+‐selective filter membrane with mi-
demonstrated a fluorescence change of ΔF/F0 = 5.0 over cropores.[55,56] The one K+ nanosensor with NIR excita-
baseline. HaloCaMP1b–JF635 (λex = 642 nm; λem = tion is engineered through encapsulating upconversion
655 nm) fused to the CKK peptide showed even higher nanoparticles (UCNPs) and K+ indicator PBFI into the
sensitivity of ΔF/F0 = 9.2 over baseline (Figure 3f). hollow core of mesoporous silica nanoparticles (MSN),
In the past decades, advanced microscope techniques and subsequently the nanosensor is enshrouded with a
have also been used for in vivo calcium imaging, for thin layer of K+‐selective filter membrane with a diam-
example, two‐photon calcium imaging (2PCI) is very eter of 5.7 Å (Figure 4a). Upon NIR irradiation, the
popular and offers unique advantages in neuroscience UCNPs emit blue light to activate K+‐bonded PBFI with
nowadays.[42] The 2P microscope allows high fluores- green emission, and the K+ nanosensor can image
cence detection resolution in high scattering brain tissue, extracellular K+ fluctuation in zebrafish and mouse
and it generates two near infrared or infrared photons brain. Similar to K+ nanosensor based on UNCPs, the
with low‐energy cooperating to induce the transition other is formed through integrating K+ indicator APG
from the ground to the excited state of a fluorescent into MSN, which is shielded using a thin layer of three‐
molecule, which occurs within a femtosecond time win- dimensional tripodal ligands (Figure 4b). Only K+ is
dow.[43] The major challenge of 2PCI is to choose the selected to diffuse into and out of the nanosensor by the
most appropriate calcium indicators. The calcium probes shielded micropores and then binds to APG with strong
used for 2P microscope mainly include chemical calcium emission around 540 nm. Besides cells and brain slices,
indicators and genetically encoded calcium indicators the K+ nanosensor can monitor K+ waves in a freely
(GECIs).[37,44] However, the chemical indicators easily moving mouse using an optic fiber. The two K+ nano-
diffuse out of cells and no longer generate fluorescence sensors provide promising methods for scientists to
signals, which limit their application to 2PCI studies.[45] monitor the K+ fluctuation of normal and pathological
GECIs are the appropriate choice for most 2PCI studies states in the central nervous system.
because of their targeting to specific cell types and pho- However, there is a dearth of NIR contrast agents that
tostability for chronic imaging over weeks or months. can effectively monitor other neurosignal‐related ions,
The Janelia GCaMP family with emission around 510 nm such as Mg2+, Na+, and Cl−. In 2015, Tang et al.
is the widely used GECI for 2PCI application (λex = addressed this issue by developing an NIR BODIPY‐based
960 nm), and the GCaMP is now on the eighth generation fluorescent probe (cBDP) that can recognize Na+ or K+
with variants optimized for high spatiotemporal resolu- and can be combined with microchip electrophoresis.[58]
tion and brightness of calcium detection.[44] Some red‐ Thus, the on‐chip electrophoresis can manipulate accu-
shifted indicators used for 2PCI, such as jRGECO1a and rate single‐cell and high‐performance separation of Na+‐
RCaMP, exhibit less sensitivity than GCaMP.[46,47] cBDP and K+‐cBDP (λex/λem = 635 nm/670 nm).
Potassium ion (K+) is also essential for maintaining Currently, the ion‐selective microelectrode methods are
physiological processes of cells, including membrane commonly used for the measurement of Na+, Mg2+ and
potential, osmotic pressure, proliferation, differentiation Cl− in vitro and in vivo.[59–61] Also, effective NIR optical
and apoptosis.[48] Especially, efflux of K+ is the key step methods for in vivo detecting these ions are still lacking.
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F I G U R E 4 Potassium indicators with K+‐selective filter micropores. (a) Schematic representation of K+ nanosensor based on UCNPs,
and the selectivity and stability of K+ nanosensor. Reproduced with permission.[55] Copyright 2020, the American Association for the
Advancement of Science. (b) Schematic design of the K+ nanosensor, and its selectivity of K+. Reproduced with permission.[57] Copyright
2020, Nature Publishing Group.
2.2 | Monitoring neuronal membrane electrical signaling transmission is the most important
potential by NIR indicators function of neurons.[63] Therefore, monitoring membrane
potential makes us better understand the function of the
Membrane potential is the key characteristic of cellular brain. The membrane potential is traditionally recorded
physiology and is dynamically controlled by a number of by electrode‐based technology, for example, the patch
ion channels and pumps.[62] As the basic physiological clamp techniques.[64] However, the electrophysiological
processes, membrane potential alteration inducing techniques suffered from some limitations due to brain
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injury resulting from the unavoidable invasiveness.[65] showed a high temporal resolution, indicating a rapid
Moreover, while a single neuron could be readily recor- response with a primary time constant of 4 ms
ded, it is difficult for high‐throughput recording.[66] As (Figure 5b). In 2016, Martisiene and colleagues further
we know, a large number of different neurons orches- found that ICG could monitor cardiac electrical activ-
trated the mammalian brain or brain regions, and just a ity.[85] Moreover, the results also showed that ICG has a
few targeted neurons couldn't elucidate the operating fast and slow dual‐component response to membrane
mechanism of higher brain function (cognition, emotion, potential changes. The fast optical signal of ICG is ob-
and etc.).[67,68] Although the electroencephalography tained with short wavelengths for λem, which is most
techniques (EEG, ECoG) could record large populations likely related to the electrochromic mechanism of ICG.
of neurons, the cellular resolution and detailed infor- The slow optical signal was detectable with the longer
mation, for example, the synaptic transmission of neuron wavelengths (λem > 800 nm), which was associated with
circuits, are loss.[69,70] the redistribution of ICG within or around the mem-
The limitation of electrophysiological recording could brane. Kang et al. found that IR‐780 perchlorate is
be overcome using optical imaging of membrane voltage, voltage sensitive, and the brain slices from the intrave-
which converts the physiological signal to fluorescent nously VSD‐injected mouse have fluorescent changes in
signal through voltage‐sensitive probes, including the response to membrane depolarization induced by the
voltage‐sensitive dyes (VSD), genetically encoded voltage changes of extracellular KCl concentration in 2021.[86]
indicators (GEVI) and hybrid voltage indicators Although VSDs obtain good sensitivity and kinetics
(HVI).[71–74] The mechanism of genetic voltage sensor property of voltage sensing, the low specificity of cell
performing is that the change of probe configuration in- type limits its spatial resolution in tissues.[87]
duces a high fluorescence intensity alteration once the GEVIs are widely used for monitoring neuronal
transmembrane voltage transient occurs.[75] Most of voltage. The core of GEVIs was designed by using voltage
voltage‐sensitive probes are developed with the excitation sensing domains which originate from microbial
and emission peaks at visible windows, which are fast rhodopsin proton pumps or voltage‐sensitive phospha-
and sensitive for neuron voltage imaging and show good tases (VSPs).[88,89] The GEVIs based on VSPs are generally
properties of spatiotemporal resolution.[76,77] However, fused to fluorescent proteins (FPs), and the fluorescent
visible light suffers from strong absorption, scattering and signal is generated by the conformational change of
autofluorescence in tissues, resulting in poor penetration voltage sensing domains caused by membrane voltage
depth. The voltage imaging in vivo should also be per- alteration (depolarization or hyperpolarization).[75] How-
formed with animals implanted with optical fibers using ever, the fluorescent signal of FPs fused to VSPs was often
an invasive way.[66,78] The NIR voltage‐sensitive probes at visible light windows. For example, circularly permuted
can obtain better characteristics of voltage imaging in fluorescent proteins (cpFPs), such as green fluorescent
deep tissues with higher signal‐to‐background ratio (SBR) protein and red fluorescent protein, generated the visible
and spatiotemporal resolution due to the low absorption, fluorescent signal.[77] Microbial intrinsically cannot
scattering and tissue autofluorescence of the NIR generate fluorescent signals and are initially used as
window.[12,79] optogenetic controls for neuromodulation.[13] The GEVIs
For VSD, the spanning wavelength of the visible light show better sensitivity and kinetics of voltage imaging, for
dyes ranges from 440 to 670 nm and show good sensitive example, Mermaid2 (λem = 563 nm) based on VSP shows
and kinetics of voltage imaging from 10% to 22% ΔF/F 48% ΔF/F per 100 mV,[90] and other visible light GEVIs,
(change of fluorescent intensity (ΔF) over baseline (F)) the series of VSFP, ArcLight and ASAP also exhibit high
per 100 mV, such as ANEPPS dyes,[80] JPW‐1114,[81] spatiotemporal resolution of voltage imaging in visible
Oxonols RH,[82] etc. Compared to visible light dyes, NIR windows.[91–93] However, most of visible light GEVIs exist
VSD provides a promising method for monitoring the inadequate SNR and high background fluorescence for
membrane voltage alteration of neurons in deep tissues. voltage imaging.[79] Therefore, developing NIR GEVIs
In the last few decades, a few NIR VSDs have been with longer wavelength will reduce background fluores-
discovered and designed. In 2014, Bezanilla's group cence and obtain adequate SNR. In 2011, Adam et al.
found that indocyanine green (ICG, λex = 780 nm, found that microbial rhodopsin could be used as a novel
λex = 818–873 nm), an NIR contrast agent with FDA GEVI scaffold and developed a series of rhodopsin‐based
approval, is voltage‐sensitive (Figure 5a).[83] It is sug- GEVIs.[94] The rhodopsin with non‐pumping mutation
gested that the fluorescence changes of ICG are roughly was fused to FPs whose fluorescence intensity was altered
linear with the alteration of membrane potential and had by the voltage‐dependent change of the photophysical
a magnitude of ~1.9% ΔF/F of the baseline fluorescence state of rhodopsin through electrochromic Förster‐reso-
per 100 mV of membrane potential change. ICG also nance‐energy transfer (eFRET).[95] In 2019, Cohen et al.
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F I G U R E 5 ICG and Quasar monitor the membrane voltage in neurons. (a) ICG fluorescence is roughly linearly dependent on voltage.
(b) ICG monitors a train of action potentials. (a, b) Reproduced with permission.[83] Copyright 2014, Elsevier Inc. (c) The constructs of co‐
expression of CheRiff and QuasAr in the cell plasma membrane. CheRiff mediates blue light‐induced depolarization, and QuasAr monitors
membrane voltage. Reproduced with permission.[74] Copyright 2014, Nature Publishing Group. (d) QuasAr3 monitors voltage alteration of
neuronal activity in the hippocampus of a walking mouse. Reproduced with permission.[84] Copyright 2019, Nature Publishing Group.
developed a series of rhodopsin‐based GEVIs with a with low background fluorescence and achieves the
maximal emission in NIR windows, which are compatible voltage imaging of neuronal activity in hippocampus of
with optogenetic stimulation for voltage imaging walking mouse (Figure 5d).[84] In addition, the specific
(Figure 5c), including QuasAr1 (715 nm), QuasAr2 promotor drives the expression of GEVIs in defined cell
(715 nm) and QuasAr3 (720 nm).[74,84] Especially, types, which guarantee high spatiotemporal resolution for
QuasAr3 exhibits high sensitivity of 40% ΔF/F per 100 mV voltage imaging in neurons.
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It is known that the native fluorescence of FPs is components, a ligand‐bingeing module binding NTs/NMs
weaker than bright organic dyes with high fluorescence and FPs.[104,105] Most of GENIs generate fluorescent
quantum yield.[96] However, the GEVIs with specific emission at the visible light window through the
promotors have the advantages of targeting specific cell conformational changes when binding to NTs/NMs, such
types for monitoring the voltage alteration with high as a series of GENIs based on bacterial periplasmic
spatiotemporal resolution. Thus, the hybrid voltage in- binding protein (PBP) or G protein‐coupled receptors
dicators, combined with the merits of GEVIs and organic (GPCRs).[106,107] GPCRs are widely distributed on the
dyes, are receiving considerable attention of scientists. In membrane and activates the downstream signaling
2019, Schreiter et al. developed an HVI indicator Voltron, pathway once binding natural targets with high speci-
which was engineered from the voltage‐sensing microbial ficity, including NTs/NMs.[108] Li's group developed a
rhodopsin Ace2 fused to a self‐labeling protein tag Hal- series of GPCR‐based GENIs, including GRABDA (dopa-
oTag by combining a series of JF dye ligands with emis- mine),[109] GRABAdo (adenosine),[110] eCB2.0 (endo-
sion maximal between 520 and 660 nm (Figure 6a).[97] cannabinoid),[111] and so forth. When binding NTs/NMs,
The Voltron generates a voltage sensitivity of −23 � 1% the GENIs generated visible fluorescence intensity
ΔF/F0 per 100 mV through FRET. Moreover, Voltron is through conformational changes of cpFPs.[103] The
successfully used in a wide range of cells and tissues and GENIs developed by Li's group show high spatiotemporal
also applied in mice and zebrafish to monitor action resolution in detecting NTs/NMs in vivo through
potential (Figure 6b). In 2021, Zou et al. developed a se- implanted fiber recording.[106] However, there is
ries of bright and sensitive hybrid voltage indicators currently a shortage of NIR GENIs available for detecting
combined with different organic dyes, including AF488, NTs/NMs. Nowadays, several NIR nGENIs are devel-
Cy3, AF594, Cy5.[98] In the study, a trans‐cyclooctene oped, including chemical dyes, cell‐based indicators and
moiety is site‐specifically conjugated to an Ace2 mutant nanomaterial‐based indicators. In 2019, Beyene et al.
through enzyme‐mediated probe incorporation and then developed an NIR‐II nGENIs, named nIRCats, which
derivatized with tetrazine‐conjugated organic dyes used the polymer‐functionalized semiconducting single‐
(Figure 6c). The hybrid voltage indicators exhibit strong wall carbon nanotubes (SWNTs) noncovalently func-
electrochromic effect, so that the fluorescence intensities tionalized with single‐strand (GT)6 oligonucleotides to
of organic dyes are dynamically modulated by the change form the NIR catecholamine selective nanosensor with
of voltage. The far‐red indicator HVI‐Cy5 can be emission of 1000–1300 nm (Figure 7a).[112] The nIRCats
compatible with optogenetic modulators or electrophys- could not only detect the dopamine (DA) and norepi-
iological imaging indicators with green/red fluorescence, nephrine (NE) release in brain slices but also be
enabling all‐optical monitoring of neuronal electrophys- compatible with DA pharmacology (Figure 7b‐c). Dinar-
iology (Figure 6d). vand et al. developed the NIR nGENIs, named NIRSer,
using a serotonin binding DNA aptamer wrapped the
functionalized SWNTs, whose designing principle is
2.3 | The detection of neurotransmitters similar to nIRCat (Figure 7d).[113] The NIRSer detects
and neuromodulators in the NIR window serotonin with a dynamic linear range in the physiolog-
ical region from 100 nM to 1 μM with 995 nm emission
Neurotransmitters (NTs) and neuromodulators (NMs), (Figure 7e).
such as dopamine, serotonin (5‐HT), GABA, etc., exert
profound roles in influencing the activity of neurons to
modulate the physiological process of brain, such as 2.4 | The NIR imaging of cerebral
emotion, cognitive, memory, sleep, etc.[99] Importantly, vasculatures
alteration of NTs and NMs levels induces the pathogen-
esis and therapy of neurological and psychiatric diseases The imaging of cerebral vasculatures profiles a visual-
and disorders.[100,101] Therefore, developing indicators izable map of brain structures and identify an under-
that enable noninvasive and long‐term monitoring of NTs standing of the molecular functions underneath.[114] To
and NMs with high spatiotemporal resolution is image the fine cerebral vasculatures, the NIR‐II imaging
necessary. (1000–1700 nm) with deep tissue penetration and high
Recently, lots of efforts are devoted to developing spatial resolution exhibits a better promising strategy for
the indicators of NTs and NMs, including genetically fine structure imaging in noninvasive modes than the
encoded NT/NM indicators (GENIs) and nongenetically imaging of short wavelengths.[115] Moreover, NIR‐II ce-
encoded NT/NM indicators (nGENIs).[102,103] The typical rebrovascular imaging can also identify the alteration of
of GENIs is developed through FRET by two vascular structure and function once cerebrovascular
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F I G U R E 6 NIR HVI of voltage imaging. (a) Schematic diagram of Voltron formation: the rhodopsin (Ace2) is fused to HaloTag with
additional sequences TS (Golgi export trafficking sequence), ER (endoplasmic reticulum export sequence) and ST (somatic targeting
sequence). (b) Voltron monitoring membrane voltage in hippocampal CA1 neurons in waking mouse. (a, b) Reproduced with
permission.[97] Copyright 2019, the American Association for the Advancement of Science. (c) The formation of HVI labeling different
fluorophores. Firstly, we made a bioorthogonal functional handle (4‐TCO) onto the central lysine residue in the peptide substrate of Ace2
rhodopsin. Secondly, fluorophores are conjugated via an inverse‐electron‐demand Diels‐Alder reaction, and voltage imaging exhibits via
eFRET. (d) Multiplexed imaging with far‐red HVI‐Cy5 and GCaMP (green fluorescent of Ca2+ indicator). (c, d) Reproduced with
permission.[98] Copyright 2021, Nature Publishing Group.
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F I G U R E 7 NIR indicators for detecting NTs/NMs. (a) The formation of nIRCats with emission of 1000–1300 nm: SWNTs
noncovalently functionalized with single‐strand (GT)6 oligonucleotides. (b‐c) nIRCats selectively detect dopamine (DA) and
norepinephrine (NE) release. Reproduced with permission.[112] Copyright 2019, the American Association for the Advancement of Science.
(d‐e) NIRSer, based on SWCNTs selectively and labeling with a serotonin binding DNA aptamer, detects the release of serotonin (5‐HT) in
real time through a change in the aptamer conformation and an increase in SWCNT fluorescence. Reproduced with permission.[113]
Copyright 2019, American Chemical Society.
disorders occur. Nowadays, a variety of NIR‐II fluo- capability of effective brain imaging to achieve a depth of
rophores for cerebrovascular imaging are developed, 3 mm beneath the scalp in the NIR‐II region. The rare‐
including inorganic and organic materials. earth nanoparticles with tunable emission wavelength
For inorganic materials, a number of NIR‐II probes in NIR‐II window.[122,123] Dai et al. developed Ce3+ doped
have been synthesized for vascular imaging in the past Er3+‐based RENPs with the emission of 1500–1700 nm,
decades, such as quantum dots (QDs), SWCNTs, rare which are able to dynamical imaging and tracking the
earth‐doped nanoparticles (RENPs), etc. Ag‐based QDs arterial blood flow in the mouse brain with a shorter
generally have a narrow direct band gap, which enables exposure time (20 ms).[124]
them to produce NIR‐II emission. Through the manipu- Organic fluorophore is another kind of critical probe
lation of size, chemical composition, and surface ligands, in biomedical research. Recently, a series of NIR‐II
researchers can obtain NIR‐II QDs with tunable emission organic fluorophores have been developed by rational
wavelengths, high biocompatibility, and high quantum design of their chemical structures. For example, by
yields, making them ideal for biomedical research pur- tuning the donor and acceptor molecules or prolonging
poses. Wang's group developed a series of Ag‐based QDs the conjugated structures, the donor‐acceptor‐donor (D‐
with NIR‐II emission, including Ag2S (λem = 1050 nm), A‐D) structure‐based probe with a narrow band gap and
Ag2Se (λem = 1350 nm), Ag2Te (λem = 1780 nm), AgAuSe NIR‐II emission can be developed for bioimaging. Dai's
(λem = 970 nm), Au‐doped Ag2Te (λem = 1600 nm) and group developed CH‐1055 with the emission of 1055 nm
etc., capped with polyethylene glycol (PEG) exhibit better that has potential to image visualize cerebral vascular
blood circulation (half‐time = 4.1 h) for imaging cerebral structure with a QY of 0.3%.[125] CH‐4T, modified by
vasculatures whose structure (about 24.3 μm) is clearly CH1055, showed a higher QY, and its interaction with
detected with micrometer resolution (Figure 8a,b), which proteins (FBS) increased the QY (about 11%), which
also have good property of monitoring angiogenesis and makes CH‐4T more biocompatible and potential for ce-
arteriogenesis in hindlimb ischemic model.[22,116,119–121] rebral vascular imaging.[126] The cyanine fluorophores
Moreover, Ag‐based QDs exhibit no toxic heavy metal also showed a high QY for NIR‐II imaging, such as ICG,
components, which shows a promising application in organic dye in NIR‐I approved by FDA for clinical
biomedical application.[21] SWCNTs also show the application, with a tail emission in NIR‐II windows
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F I G U R E 8 NIR‐II probes for cerebrovascular imaging. (a, b) Ag2S QDs with NIR‐II emission for imaging cerebral vasculatures.
(a) Reproduced with permission.[116] Copyright 2012. (b) Reproduced with permission.[22] Copyright 2014. (c) FD1080 imaging cerebral
vasculatures beyond 1500 nm. Reproduced with permission.[117] Copyright 2018. (d) AIEgen TQ‐BPN for microscopic imaging of the mouse
brain vasculature at various depths. Reproduced with permission.[118] Copyright 2018. (a, b, c and d) Wiley‐VCH.
exhibits higher brightness than most NIR‐II fluorophores dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC), which
for cerebral vessel imaging.[127] A number of organic dyes makes a redshift of the fluorophores with absorption and
inspired by ICG have been developed for further emission peaks of 1360 nm/1370 nm.[129]
improving NIR‐II imaging, such as IR‐12N3, Aggregation‐induced emission luminogens (AIEgens)
IRDye800.[128] The organic macromolecular conjugated are novel NIR imaging dyes for brain vessel imaging.[130]
polymers were extended to the NIR‐II windows. FD‐1080 AIEgens exist as a unique phenomenon suggesting a
with large π‐system of the benzo[c,d]indolium hetero- family of luminogens with weekly emission or non‐
cycle shifted the excitation/emission peak at 1064 nm/ emission in the molecularly dispersed state showing
1080 nm and is performed non‐invasive and high‐ markedly boosted fluorescence in the aggregation
resolution for cerebral vasculature imaging state.[131] Since the first report by Tang's group, a series of
[117]
(Figure 8c). Furthermore, FD‐1080 showed an excel- AIEgens were developed for the application of biomedical
lent J‐aggregation effect using the film dispersion method imaging. The high spatiotemporal resolution of NIR‐II
to induce the self‐assembly of FD‐1080 and 1,2‐ windows attracts many scientists devoted to the
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development of the NIR‐II AIEgens. Wu et al. developed The curcumin analog‐based NIR probes of Aβ plaques,
the first semiconducting polymer NIR‐II AIEgens, named AD‐1 (λem = 705 nm) and CARNAD‐3 (λem = 720 nm),
P3c, used for non‐invasive through‐skull cerebral exhibited good blood brain barrier (BBB) penetrating
vascular imaging exhibiting a maximum emission at ability and low cytotoxicity of monitoring the patholog-
1083 nm.[132] Xiao et al. designed NIR‐II AIEgens, named ical process of soluble and insoluble Aβ species in APP/
HL3, that showed high spatial resolution of brain vessel PS1 mouse (Figure 9a).[142,147] Cui et al. developed a se-
imaging with the emission peak at 1050 nm.[133] More- ries of Aβ plaque probes with a conjugated π‐electron
over, the HL3 with long tail emission of 1500 nm showed chain, named DANIRs.[143] DANIR‐2c is the optimal
a better spatial resolution with the high SBR with probe, exhibiting 12 folds increase of brightness
1500 nm long pass (LP) imaging. Tang's group developed compared with Tht, that can penetrate the BBB for Aβ
AIEgen TQ‐BPN dots with NIR fluorescence and two‐ plaques imaging with the emission peak of 655 nm
photon fluorescence scanning which precisely monitors (Figure 9b).
brain blood barrier (BBB) and photothrombotic ischemia TBI is a major cause of death and disability world-
(PTI) in brains (Figure 8d).[134] wide.[148] After TBI, a series of oxidative stress markers,
including ROS, RNS, RSS, whose large productions also
present the second injury.[149] In 2020, Wang's group
2.5 | The NIR approaches for developed a QD‐based ONOO−‐responsible sensor
neuropathological detection through a FRET mechanism.[144] The NIR‐II ROS sensor
used ONOO−‐activatable chromophore A1094, an NIR
The occurrence and development of diseases and disor- absorber, conjugated with Ag2S QDs, named V&A@Ag2S
ders in the central nervous system are usually accompa- (Figure 9c). Due to the FRET between A1094 and Ag2S
nied by the expression changes of some molecular QDs, the NIR‐II ROS sensor remained turned off. Upon
markers.[135] For example, the high deposition of insol- binding to ONOO−, A1094 was bleached and the NIR‐II
uble Aβ and hyperphosphorylation of Tau protein are the fluorescence of Ag2S QDs turned on. Some other NIR
neuropathological characteristics of Alzheimer's dis- ROS sensors have also been developed for detecting
ease.[136] A large quantity of reactive oxygen species oxidative stress markers in brain diseases and disorders.
(ROS) are generated once traumatic brain injury (TBI) Zhang et al. developed a highly reactive oxygen species
occurs, which also induces secondary injury and leads to (HROS)‐responsive ratiometric near‐infrared‐II (NIR‐II)
disability and death.[137] In particular, it is an urgent nanoprobe in which the system contains the IR‐783 dye
clinical need for non‐invasive high‐resolution imaging and lanthanide‐doped nanoparticles, named IR‐
techniques for neuropathological examination. There- LnNPs.[145] The IR‐783 exhibits an intense absorption
fore, the NIR imaging with deeper tissue penetration and emission peak around 808 nm, and the LnNPs are
ability and low tissue autofluorescence provides an synthesized with the composition, NaYbF4:5%Er,5%
innovative strategy for neuropathological detection. Ce@NaYF4:20%Nd with an emission peak around
Nowadays, the neurodegenerative diseases (NDs), 1550 nm (Figure 9d). The NIR‐II fluorescence of LnNPs
including Alzheimer's disease (AD), Parkinson's disease at 1550 nm is reduced with the concentration of ROS
(PD), Huntington's disease (HD) and Amyotrophic lateral increasing, accompanied by a decrease fluorescence in-
sclerosis (ALS), are incurable nervous disorders, as a tensity of IR‐783 at 808 nm. Moreover, the LnNPs could
consequence of progressive deterioration of the brain.[138] accumulate at lesion sites by sensing the impaired BBB in
It is suggested that NDs share a common mutation of the ischemic area and then responding to ROS, allowing in
cytosine‐adenine‐guanine (CAG) nucleotide triplet repeat vivo imaging.
resulting in the translation of polyglutamine tract in Brain tumor exhibits higher malignancy than other
misfolded proteins, which induces abnormal degradation kinds of tumors, especially the gliomas. Due to the high
and aggregation of proteins.[139] Especially for AD, Aβ ability of migration and invasion of brain tumors, it is
deposition and hyperphosphorylation of Tau protein difficult to identify their margins during surgical resec-
resulting from the mutation plays vital roles in the tion.[150] The ideal brain tumor probes can guide real‐
development of AD.[140] Moreover, the PD, HD and ALS time intraoperative surgery for complete resection to
undergo the similar neuropathological features. Some avoid tumor recurrence, which requires high spatiotem-
NIR organic dyes have been designed by researchers to poral resolution of tumor imaging. The NIR probes with
target Aβ plaques. The classic Aβ plaques probes are long excitation wavelength largely improve imaging
Thioflavin‐S (Ths) and Thioflavin‐T (Tht), but the bind- quality due to the lower scattering and autofluorescence
ing of Aβ plaques with them demonstrates the visible background of NIR light compared to visible light. For
fluorescence window at the emission about 480 nm.[141] example, the NIR probe ICG approved by FDA for clinical
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F I G U R E 9 NIR indicators of neuropathological detection. (a) AD‐1 specifically binds to Aβ plaques in vitro and in vivo. Reproduced
with permission.[142] Copyright 2021. (b) DANIR‐2c monitors Aβ plaques in AD mouse. Reproduced with permission.[143] Copyright 2014.
(c) V&A@Ag2S emission in NIR‐II windows shows ROS levels in TBI models through the FRET mechanism. Reproduced with
permission.[144] Copyright 2020, Wiley‐VCH. (d) The ratiometric near‐infrared‐II (NIR‐II) nanoprobe highly IR‐LnNPs responses to
reactive oxygen species (HROS) in ischemic stroke. Reproduced with permission.[145] Copyright 2021. (a, b and d) American Chemical
Society. (e) Gd‐Ag2S nanoprobe combines the advantages of the deep tissue penetration of enhanced magnetic resonance imaging of Gd
and high spatiotemporal resolution of NIR‐II fluorescence of Ag2S QDs for targeting brain tumors. Reproduced with permission.[120]
Copyright 2015, Wiley‐VCH. (f) TRAD, wrapping anti‐drug DOX and labeling the T7 peptide for both the blood‐brain tumor‐barrier
penetration and glioma targeting, brings high imaging sensitivity and antitumor therapy to both the cerebral and cerebellar gliomas.
Reproduced with permission.[146] Copyright 2022, the American Association for the Advancement of Science.
application significantly benefits surgeons to distinguish good properties of brain tumor imaging or image‐guided
tumor margins.[151] Other NIR contrast agents of brain therapy.[152–154] Moreover, the NIR contrast agents
tumors, such as IR‐780, IR‐700, CH1055, etc., also show combining with other functional groups can obtain more
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property for identifying margins of brain tumors. Wang’ treatment, including AD, PD, depression, etc.[159]
group developed a dual‐modality nanoprobe, Gd‐DOTA‐ Therefore, it attracts many scientists to explore a wide
Ag2S QDs, which combined the advantages of the deep variety of implantable and noninvasive‐based techniques
tissue penetration of enhanced magnetic resonance im- in the past decades, such as electrical, magnetic, chemi-
aging of Gd and high spatiotemporal resolution of NIR‐II cal, acoustic and optical neuromodulation.[160] However,
fluorescence of Ag2S QDs (Figure 9d).[120] The novel these approaches come with their unique advantages and
strategy is a promising “Detection and Operation” system disadvantages. The electrical stimulation shows high
for clinical image‐guided tumor dissection. Moreover, the temporal resolution with implanted electrodes.[161]
NIR probes of integrated diagnosis and therapy have also Optogenetic neuromodulation, the most popular optical
been developed for brain tumor imaging (Figure 9e). neuromodulation at present, exhibits high spatiotemporal
Kong et al. developed an NIR persistent luminescence resolution with fiber tract invasion.[162] However, both of
nanoparticle, named TRAD (DOX‐ZGOCS@MSN@RBM‐ them are involved in the implantable stimulator, causing
T7), with a dual function of imaging and therapy of ce- the immune response and scar formation around the
rebral and cerebellar gliomas.[146] TRAD, containing the stimulator interface.[163] Magnetic stimulation exits
T7 peptide for both the blood‐brain tumor barrier (BBTB) noninvasive control of neuron systems with low spatio-
penetration and glioma targeting, brings high imaging temporal resolution.[7] An ideal neuromodulation needs
sensitivity and antitumor therapy to both the cerebral and both high spatiotemporal resolution and noninvasive.
cerebellar gliomas (Figure 9f). NIR‐II windows are favorable for less light scattering and
deep tissue penetration, which provides a promising tool
for neuromodulation.[16] At present, it lacks ion channels
2.6 | The clinical application of NIR or receptors that can respond to NIR‐II light. For devel-
approaches for functional brain imaging oping neuromodulation strategies based on NIR‐II win-
dows, variable kinds of NIR‐II nanotransducers are
Currently, the most successful NIR approach used for produced to regulate the physiological process of neurons
clinical brain imaging is the functional near‐infrared under NIR‐II irradiation.[164]
spectroscopy (fNIRS). Over the past few decades, the
fNIRS have been successfully employed for monitoring
and imaging the functional hemodynamic condition of 3.1 | Manipulation of neural electrical
the human brain.[155] By irradiating the brain with NIR activity by NIR
light, which is capable of penetrating through the skull
and scalp up to several centimeters, and subsequently So far, there are no ion channels that can respond directly
detecting the diffused light using a detector, fNIRS is able to NIR light. To develop the methods of NIR‐triggered
to measure regional cerebral blood flow changes within neuromodulation, the nanotransducers that respond to
the brain in real‐time by tracking changes in concentra- NIR are brought, including up‐conversion nanoparticles
tions of cerebral hemoglobins such as oxygenated (HbO), (UCNPs), photothermal (PTT), and photoacoustic (PA)
deoxygenated (HbR), and total (HbT).[156] Although many nanotransducers.
studies involving the propagation of NIR light in the hu- In 2016, Han et al. developed dye‐sensitized UCNPs,
man brain have been conducted, the accuracy of fNIRS IR‐806‐sensitized β‐NaYF4:20%Yb3+, 2%Er3+@β‐
3+
remains a challenge for researchers due to several reasons, NaYF4:10%Yb , with the emission in visible windows
including the presence of extracerebral tissue information activated ReaChR (a traditional optogenetic ion channel)
within the detected signal, as well as the interference of for manipulating the depolarization of hippocampal
changes in cerebral blood flow on Hb concentration.[157] neurons with the excitation of 808 nm.[165] However,
whether the approach could achieve the manipulation of
neuron activity of deep brain tissue in vivo remains un-
3 | THE APPLICATION OF NIR LIGHT clear. In 2019, McHugh and his colleagues firstly ach-
FOR NEUROMODULATION ieved the wireless manipulation of neuron activity in
vitro and in vivo. They chose silica‐coated UNCPs (NaYF4
Clearly understanding the transmission and processing of nanocrystals co‐doped with Yb3+/Tm3+) with stable
neuronal circuit is a great challenging.[158] The tech- chemical property that conversed 980 nm to blue light,
niques of neuromodulation provide tools for researchers which overlapped the absorption of ChR2.[166] Upon
to modulate and interface with the nervous system for transcranial NIR laser irradiation, the genetically tagged
manipulating the neuronal circuits, which also supplies neurons with ChR2 are depolarized by blue light emitted
promising approaches for brain diseases and disorders from a local injection of UCNPs (Figure 10a). To explore
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the in vivo utility of UCNPs‐mediated optogenetics, the 1064 nm, and it is suggested that 1064 nm light offers the
transgenic mice with dopamine (DA) neurons condi- greatest tissue penetration through reduced scattering
tionally expressed ChR2 in the VTA brain region were and absorption in brain tissue. Moreover, the photo-
generated, and it suggested that the DA neurons in VTA thermal conversion efficiency of MINDs was 71% at
are selectively triggered by NIR light in the transgenic 1064 nm (10 mW/mm2) and the MIND solution (1.8 mg/
mice since the elevated expression of c‐Fos and DA mL) reached 39°C within 1.1 s, which suggested that
transients in VTA are determined in the same treated MINDs possess good characteristics of photothermal
mice (Figure 10b,c). Researchers also found that NIR‐ conversion efficiency. For better neuromodulation ef-
mediated UCNP optogenetics could induce brain oscil- fects, the motor cortex neurons (0.5 mm beneath skull)
lations by activating inhibitory neurons in the region of are selectively overexpressed TRPV1 by injecting AAV5‐
the medial septum (MS). Furthermore, the UCNP opto- eSyn‐TRPV1‐p2A‐mCherry, followed by MIND injection
genetics could silence seizure by inhibition of hippo- in the same region 3–4 weeks later; the latency time of
campal excitatory neurons and trigger memory recall. unilateral circling induced by wide‐field 1064 nm irradi-
Therefore, the UCNP‐mediated optogenetics provided a ation (8 mW/mm2) was 5.0 � 1.5 s (Figure 10e). Qin et al.
promising method for the manipulation of neuron ac- suggested that the temporal resolution of the photo-
tivity in a noninvasive and wireless way. thermal system depends on the power density of NIR‐II
There existed a number of temperature‐sensitive ion illumination, and the higher temporal resolution with
channels on the membrane of neurons, suggesting that millisecond response time could be reached under a po-
photothermal stimulation is an alternative to manipulate wer density of 105–106 mW/mm2 illumination. However,
neuronal activity.[169,170] The nanotransducers converting high power density of NIR‐II illumination leads to the
NIR light into mild heat at the neuronal membrane could thermal damage of the brain. MINDs illuminated by
activate temperature‐sensitive ion channels with NIR 1064 nm also activated deep brain region ventral
irradiation, mediating neuron activity.[171] A variety of tegmental area (VTA, >4.0 mm beneath skull) under a
photothermal nantransducers have been developed, power density of 10 mW/mm2, proved by the fact that the
including inorganic (Au nanorods, metallic oxides, mice injected both MINDs and TRPV1 show strong
copper‐based semiconductor, rare earth ions doped preference for the NIR‐II illuminated arm terminal in Y
nanocrystals, and etc.), small organic molecules (cyanine maze. Although the high millisecond temporal resolution
dyes, organic polymers, and etc.).[172] These photo- cannot be reached in the TRPV1 photothermal system
thermal nanotransducers shows broad NIR absorption under low power density, it provides a promising method
bands allowing excited by different wavelengths of NIR for wireless optogenetics with minimal invasion. Fang
windows. For inorganic photothermal agents, Pu et al. et al. also developed an NIR‐II‐induced photothermal
synthesized a semiconducting polymer SPN1bc neurostimulation via bioinspired nanovesicles (PANIP‐
(λex = 780 nm) that was conjugated with anti‐TRPV1 ES@AOT), which achieves wireless behavior modula-
antibodies to target TRPV1 ion channels, and the tar- tion.[174] Moreover, the nanovesicles can provide trans-
geting system permitted quick diffusion of generated heat cranial NIR‐II photoacoustic imaging (PAI), enabling
for opening TRPV1 channels upon 808 nm irradiation, transcranial NIR‐II photothermal neurostimulation
which induces Ca2+ influx immediately in neurons.[171] guided by NIR‐II PAI.
Nam's group also found that hippocampal neurons Acoustic neuromodulation is also an emerging
receiving photothermal heating from AuNPs encounter noninvasive and wireless method for the manipulation of
the inhibitory regulation with the irradiation of neuron activity.[175] It is suggested that acoustic could
785 nm.[173] However, most inorganic photothermal evoke action potentials in vitro and induce behavioral
nanotransducers have poor biodegradability and other response in vivo.[176] The targets of acoustic waves for
adverse aspects, which limits its exploration of in vivo regulating neuron activity are mechanosensitive ion
study. Compared with inorganic nanomaterials, organic channels, such as TRPV4, Pizeol, etc.[177] In 2021, Yang
photothermal nanotransducers exhibit better biocom- et al. developed photoacoustic nanoparticles (PANs) with
patibility and low cytotoxicity.[172] In 2022, Hong and the the absorption peak of 1100 nm, a semiconducting
colleagues achieve the manipulation of neuron activity polymer bis‐isoindigo‐based polymer nanotransducers
with an organic photothermal nanotransducer in vitro generating acoustic signals upon NIR‐II light excitation,
and in vivo (Figure 10d).[167] They design organic pho- conjugated with anti‐TRPV4 antibodies that targeted
tothermal transducer MINDs, a π‐conjugated semi- TRPV4 channels on the neuronal membrane
conducting polymer core of pBBTV coated with PLGA‐ (Figure 10f).[168] It is demonstrated that Ca2+ imaging by
PEG, has a good ability of water solubility and biocom- the GECI GCaMP6f showed that PANs successfully
patibility. MIDNs exhibits efficient absorption around activated neurons in vitro under the illumination of
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F I G U R E 1 0 Neuronal manipulation of NIR light using nanotransducers. (a) UCNPs‐mediated optogenetics. (b) Neuromodulation of
neurocircuit VTA‐NAc using NIR stimulation of the VTA. (c) c‐Fos expression of the VTA after transcranial NIR stimulation, indicating the
high spatial resolution of NIR‐mediated neuromodulation. (a, b and c) Reproduced with permission.[166] Copyright 2018, the American
Association for the Advancement of Science. (d) NIR‐II photothermal activation of TRPV1 using MINDS, a photothermal nanotransducer.
(e) The temporal resolution of NIR‐II photothermal neuromodulation. (d, e) Reproduced with permission.[167] Copyright 2022, Nature
Publishing Group. (f) Acoustic neuromodulation through photoacoustic nanotransducer excited by NIR‐II light. (g) Electrophysiological
recording under NIR‐II light irradiation. (f, g) Reproduced with permission.[168] Copyright 2021, Elsevier Inc.
1064 nm under nanosecond laser power of 70 W/cm2 and train at 21 mJ/cm2 at 1030 nm. Electromyography (EMG)
a train of 10 pulses over 3 ms. Moreover, it is demon- was recoded to evaluate the behavior response of the
strated that the motor cortex with injection of PANs stimulation, which suggested that a response with an
produced a strong LFP response under a 3 ms laser pulse amplitude of 428.8 � 119.0 μV and a delay of
YIN ET AL.
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127.8 � 24.3 ms was detected with 200 ms laser pulse moiety, and then the caged molecules are released at the
train at 1030 nm, and the control group on the contra- defined locations and times upon illumination of light at
lateral side without PAN injection shows no response certain wavelength.[183,184] Zhang's group developed a
under the laser irradiation (Figure 10g). This indicates series of NIR‐light delivery systems containing UCNPs
that photoacoustic stimulation is also a potential method coloaded with anti‐STAT‐3 photomorpholinos and
for the manipulation of neuron activity in a wireless and TPPS2a (a photosensitizer).[185] The UCNPs emitted both
non‐invasive mode. UV and visible light, and UV light photocleaved the
Recently, it is reported that the NIR light solely can also photomorpholinos to release anti‐STAT‐3, while the
manipulate the electric activity of neurons with femto- visible light activated TPPS2a for endosomal escape and
second pulse irradiation.[178–180] He et al. found that the enhance photomorpholino delivery. In 2020, Qin's group
ultrafast laser with low‐power femtosecond pulses without developed mechanoresponsive nanovesicles (Au‐m‐nV)
photosensitive proteins or any other exogenous compo- coated with gold, which consisted of liposomes made from
nents can directly control store‐operated calcium chan- the artificial phospholipid Rad‐PC‐Rad for bioactive
nels, which is called femtoSOC methods.[178] They use a molecules delivery into deep brain regions.[186] After NIR
multiphoton confocal microscope, equipped with a light irradiation, Au‐m‐nV generates nanomechanical
femtosecond pulse laser (700 nm, 1.4–4.0 mW), to stress and leads to the liposome breaking and releasing
manipulate cells with femtoSOC and take cell imaging the vesicle cargos in sub‐seconds. The high photosensitive
during performing femtoSOC (Figure 11a). Interestingly, delivery system could deliver biological molecules to a
femtoSOC obviously induces Ca2+ influx in various types depth of 4 mm in mouse brain with 740 nm irradiation,
of cells, and the doubt that photothermal effects contribute which is a promising method for preventing the photo‐
to Ca2+ influx is also clarified because no cells show Ca2+ toxicity of UV and visible light for brain injury. In 2021,
rise under a 10 times higher power and continuous‐wave Ferreira et al. also developed an NIR‐activatable Cre
laser irradiation. The study of the molecular mechanism recombinase systems consisting of UCNPs which were
shows that femtoSOC induces Ca2+ influx through Orai1 conjugated with Cre recombinase enzymes through a
channels, and the polymerization of Orial1 channels into photocleavable linker and an endolysosomal escape agent
store‐operated calcium channels (SOCs) occurs upon (HCQ) on the surface (Figure 12a).[187] The system ach-
femtosecond pulses of laser irradiation (Figure 11b). ieved gene editing of cells in the subventricular zone
Moreover, Shu et al. developed midinfrared stimulation (SVZ) region to express the YFP protein through the loxP
(MIRS) method for neuromodulation with the laser radi- cassette after exposure to NIR. Moreover, Cre‐UCNPs
ation between 5 and 11 μm of 100–500 ns pulses.[179] It is successfully manipulated gene editing of DA neurons in
suggested that MIRS modulates the action potential in the VTA region, and then the edited cells were activated
neurons through increasing voltage‐gated K+ currents for control of reward and reinforcement with optogenetics
selectively (Figure 11c,d) because the resonance vibration activation. Many systems with the uncaging delivery
of –C=O bonds in K+ channels can be specially induced by methods usually depend on the photosensitivity of bio-
MIRS, whereas the carboxyl group of –COO‐ in Na+ logical cages that are photocleaved by UV or visible light
channels have no response (Figure 11e). emitted by UCNPs. Although the system has a good effect
on the expression of gene expression using NIR, uncaging
with UV or visible light is limited by the photo‐toxicity
3.2 | The gene expression of neurons and tissue penetration.
mediated by NIR Some researchers also developed the UCNPs‐
mediated optogenetic nanoplatforms for regulating
The alteration of gene expression plays central roles in gene expression in NIR windows. Zhou et al. developed
controlling the physiological process of cells, and the an NIR‐inducible optogenetic platform, named Opto‐
wireless manipulation of gene expression should be also CRAC, that selectively controls Ca2+ influx and the
promising approaches for neuromodulation.[181] NIR Ca2+‐related signaling pathway.[189] Opto‐CARC com-
windows are also the ideal wireless trigger for deep tissue prises the UCNPs, NaYF4: Yb, Tm@NaYF4, with blue
penetration, which controls gene expression at defined emission and NIR excitation conjugated with the strep-
locations and times to minimize the off‐target effects. tavidin, which targets the cells expressed recombinant
Caged release is also one of the most widely used protein ORAI1streptag (ORAI1 Ca2+ channel inserted with
method for manipulating the expression of biological streptavidin‐binding tag) and LOVSoc (photoswitch
molecules, including nucleic acids, neurotransmitters, LOV2 domain inserted into stromal interaction molecule
secondary messengers, enzymes and other molecules.[182] 1 cytosolic domain, STIM1‐CT). The blue light emitted
The photocaged release system is involved in a photolabile by UCNPs activates LOVSoc for opening the ORAI1
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F I G U R E 1 1 Neuromodulation with femtosecond light. (a) Multiphoton confocal microscope, equipped with a femtosecond pulse
laser, manipulates cells with femtoSOC and takes cell imaging of monitoring Ca2+ fluctuation during femtoSOC. (b) FemtoSOC mediates
Ca2+ fluctuation via polymerization of Orial1. (a, b) Reproduced with permission.[178] Copyright 2021, Nature Publishing Group.
(c) Midinfrared stimulation (MIRS) regulates the action potential in neurons with 100–500 ns. (d) MIRS selectively increase potassium
currents. (e) MIRS specifically induces resonance vibration of –C=O bonds in K+ channels. (c, d, e) Reproduced with permission.[179]
Copyright 2021, Springer.
Ca2+ channels, thus resulting in Ca2+ influx to trigger system by engineering photosensitive constructs opti-
the gene expression of Ca2+‐related signaling pathway. mized IsPadC‐PCM (photosensory core module of Idio-
Chang et al. also developed a similar approach of using marina sp. A28L phytochrome‐activated diguanylyl
UCNPs‐mediated optogenetics to regulate the apoptotic cyclase) variant, named iLight, which is the minimal
signaling pathway.[190] The photosensitive element is light‐sensing module in photochromes (Figure 12b).[188]
designed using the arabidopsis flavoprotein crypto- To validate iLight‐induced gene expression in primary
chrome 2 (Cry2) fused to Fas‐associated protein with neurons, The AAV was packaged with iLight system and
death domain (FADD), which will quickly interact with the reporter mCherry fluorescent protein, which is driven
its partner Cib1 after blue light illumination. Upon NIR by the promotor of calcium/calmodulin‐dependent ki-
irradiation (980 nm), the blue light emitted by UCNPs nase II (CaMKII) specifically expressed in cortical and
induces Cry2‐FADD to interact with Cib1‐Fas. Fas hippocampal excitatory neurons. After transduction with
binding to its adaptor FADD at the same time could AAVs in vitro for 5 days and then irradiation with 660 nm
activate the caspase apoptotic signaling pathway. irradiation (500 μW/cm2, 30 s On, 180 s Off) for 5 days to
Other novel optogenetic systems have also been induce the reporter expression. Consequently, they also
developed by researchers for optogenetic gene expression. successfully multiplexed the iLight optogenetic system
The photosensitive molecules in optogenetic systems with channelrhodopsin (red light sensitive ion channels).
often contain several components of large size and After inducing the expression of channelrhodopsin with
multidomain structure.[191] In 2021, Verkhusha et al. 660 nm irradiation, photocurrents were recorded by
developed a single‐component NIR‐inducible optogenetic 505 nm light.
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F I G U R E 1 2 The gene expression of neurons mediated by NIR. (a) An NIR‐activatable Cre recombinase system consisting of UCNPs
conjugated with Cre recombinase enzymes through a photocleavable linker and an endolysosomal escape agent (HCQ) on the surface.
Reproduced with permission.[187] Copyright 2021. (b) iLight system engineered with photosensitive constructs optimized with IsPadC‐PCM
variant, and the AAV packaged with iLight system induces the expression of the mCherry reporter under irradiation with 660 nm.
Reproduced with permission.[188] Copyright 2022. (a, b) Nature Publishing Group.
3.3 | Neurogenesis mediated by NIR Interestingly, some studies have indicated that light‐
triggered neurogenesis is a promising method for treat-
Neurogenesis plays an important role in the repairment ing brain diseases in a nongenetic and noninvasive way.
of brain diseases and disorders, which provides prom- In 2019, Li et al. found that blue light modulated
ising strategies for neuron replacement therapy for brain neuronal/glial differentiation of NSCs through activating
disease, including brain injury, degenerative neurological non‐visual opsin The melanopsin (Opn4)/transient re-
disease.[192] It is suggested that during the development ceptor potential channel 6 (TRPC6).[194] The NIR‐
of the mammalian, neurogenesis from neuron stem/ inducible differentiation system was also developed for
progenitor cells (NSCs/NPCs) continues throughout life neuronal/glial differentiation of NSCs in vivo using
in the central nervous system, including neuron prolif- UCNPs with blue light emission under 980 nm irradia-
eration, maturation, synaptic integration and etc.[193] tion. Bian et al. developed a multifunctional nanocarrier
Recently, researchers have devoted considerable efforts for controlling differentiation and long‐term tracking of
to manipulate the neurogenesis of NSCs/NPCs and human mesenchymal stem cells (hMSCs) using a pho-
developed related therapeutic approaches of brain tocaged method mediated by UCNPs.[195] Upon NIR
diseases. irradiation, the differentiation‐inducing kartogenin
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(KGN) that is conjugated with a photocaged linker on the inflammation type) and increases cerebral vessel density
surface of UCNPs is released to induce hMSCs differen- to degrade Aβ plaques in AD mouse (Figure 13b). Grillo
tiation in vitro and in vivo. Moreover, it indicates that the et al. found that 1070 nm light not only promotes Aβ
proliferation of cells is also influenced by light. Hamblin plaque degradation but also inhibits the phosphorylated
et al. found that 660 and 810 nm irradiation enhances the levels of tau protein.[207] Lima et al. demonstrated that
cell proliferation, but 415 nm, 540 nm PBM decreases the 1064 nm laser improves the cognitive in older adults.[208]
proliferation of the cells at 3 J/cm2.[196] Abrahamse et al. Moreover, it is reported that PBM based on NIR light is
also found that after iASCs differentiated into free‐ also used for TBI and PD treatment in basic and pre-
floating neural stem cell aggregates (neurospheres), NIR clinical research.[209] These all indicated that PBM of NIR
(825 nm) irradiation could induce neurospheres to neu- light is a promising therapeutic method for neurological
rons at 5 J/cm2, 10 J/cm2, and 15 J/cm2.[197] The mech- diseases.
anism of differentiation induced by light may be involved NIR light is also used as a monitoring tool for nano-
in the alteration of ROS and metabolism in cells, which medicine precise delivery. Wang’ group developed a novel
shows that high levels of ROS are inhibited, and low and therapeutic method for monitoring the engineered NSCs
moderate ROS promotes cell proliferation, and metabo- for AD treatment using Ag2S QDs with NIR‐II emission
lites are also changed by redox status in favor of cellular (Figure 13c).[206] The engineered NSCs genetical stably
proliferation and differentiation. expressing neprilysin (NEP), a key protease for Aβ
degradation, and a highly efficient gene and drug delivery
nanoformulation (PBAE‐PLGA‐Ag2S‐RA‐siSOX9, PPAR‐
3.4 | The treatment of brain diseases siSOX9) containing SOX9 siRNA‐expression plasmid,
and disorders by NIR retinoic acid (RA), and Ag2S QDs are also applied to the
engineered NSCs for enhancing neuronal differentiation
In the past decades, although a large number of scientists of NSCs via the synergistic effect of the Wnt/β‐catenin
devote to the basic and clinical research on brain diseases and RA signaling pathways and precisely monitor NSC
and disorders, including neurological diseases (AD, PD, transplantation in real time using Ag2S QDs with NIR‐II
HD, TBI, and etc.) and psychiatric disorders (depression, emission. The multifunctional NSCs ameliorated cogni-
schizophrenia, autism and etc.), most of them still have tive and memory deficits of AD and achieved 6‐months
no incurable approaches, and as more and more people long‐time therapy (Figure 13d). Chen et al. developed
suffer from brain diseases, which will bring a heavy an NIR radiation‐assisted drug delivery nanoplatform
burden to the world.[198] Recently, it is suggested that for PD treatment, which consists of a zeolitic imidazo-
photobiomodulation (PBM) is a promising therapeutic late framework 8‐coated Prussian blue nanocomposite
method for brain diseases and disorders treatment.[199,200] encapsulated with antioxidant quercetin (QCT), named
Especially, NIR light with the ability of low scattering and ZIF‐8@PB‐QCT.[210] Since the previous study demon-
high penetration in deep brain tissue provided a nonin- strated that a control of 41–43°C promoted BBB perme-
vasive way for brain disease treatment. ability, the nanomedicine could penetrate through BBB
PBM is a noninvasive promising method for brain and induced enrichment in the brain using the photo-
disease therapy, which has been used to promote neu- thermal effect upon NIR (808 nm) irradiation. The QCT
roprotection and repairment of brain injury through released from ZIF‐8@PB‐QCT reduces the oxidative
activating endogenous mechanisms of neurons with low‐ stress levels and improves the mitochondrial dysfunc-
power light.[201,202] For example, many studies indicated tion. Moreover, ZIF‐8@PB‐QCT restored dopaminergic
that PBM with NIR windows has a positive effect on Aβ neuronal damage and PD‐related behavioral deficits in
plaque clearance in plasma, cerebrospinal fluid and brain MPTP‐induced PD mice. Li et al. designed a photo-
in AD mouse.[203] NIR light with different frequencies thermal system, Cu2‐xSe‐anti‐TRPV1 nanoparticles (CS‐
also has different effects on the AD. Tsai et al. demon- AT NPs), activated by NIR light (1064 nm) for the clear-
strated that 40 Hz light flicker (at gamma oscillation) ance of α‐synuclein, the major pathogenic component of
decreases the levels of Aβ plaques in the visual cortex PD, through enhancing the autophagy of microglia by
through entraining the disrupted Gamma oscillation in opening TRPV1 channels targeted by CS‐AT NPs.[211]
5XFAD mice.[204] Wei et al. found that the cognitive and
memory impairment in AD mouse is ameliorated by NIR‐
II light (1070 nm) through activating microglia and 4 | CONCLUSIONS AND PERSPECTIVE
astrocyte for Aβ clearance at the low power density of
25 mW/cm2 (Figure 13a).[205] Moreover, 1070 nm pulsed NIR light‐based techniques have offered the possibility to
at 10 Hz reduces perivascular M1‐micorglia (pro‐ monitor and modulate the brain function with
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F I G U R E 1 3 Neurodegenerative diseases treatment by NIR light. (a) 1070 nm light irradiation apparatus, and 1070 nm light improves
the defects of cognition and memory in AD mouse. (b) 1070 nm light mediates M1‐microglia (pro‐inflammation type) and degrades Aβ
plaques in AD mouse. (a, b) Reproduced with permission.[205] Copyright 2021, Nature Publishing Group. (c) Monitoring the engineered
NSCs for AD treatment using Ag2S QDs with NIR‐II emission. (d) Ag2S QDs monitor NSC transplantation in real time with NIR‐II
emission, and the engineered NSCs ameliorate cognitive and memory deficits of AD. (c, d) Reproduced with permission.[206] Copyright
2021, Wiley‐VCH.
exceptional spatiotemporal precision due to the reduced animal studies. It is known that the penetration depth of
absorption and scattering of NIR light in biological tis- light in the brain is generally dependent on its wavelength
sues. Thus, the NIR approaches have been successfully according to the physical principles of the interaction
used to explore the mechanism of how the brain works as between light and tissues (Figure 2). It has been found
well as the diagnosis and treatment of brain disorders. that, for light with wavelengths between 400 nm and
Although important progresses in neuroimaging and 1800 nm, the maximum penetration depth in the brain
neuromodulation have been achieved by NIR light‐based was achieved by the light around 1070 nm (Figure 2c,
approaches, many challenges remain both in funda- d).[15] A ~20 fold of light attenuation over a depth of 4 mm
mental brain research and future clinical translation. was found at 1070 nm, while that for 980 and 470 nm was
~102 and ~109 fold attenuation, respectively. Therefore,
further development of probes with higher absorption or
4.1 | The penetration depth emission efficiency in such NIR‐II windows using strate-
gies such as energy band regulation is an important way to
Although a tissue penetration depth of more than 1 cm achieve higher tissue penetration depth.
has been achieved with the NIR‐II light, it is still inade- On the other hand, the magnetic field‐ or ultrasound‐
quate for the study of deep brain tissue, especially in large activated optical methods overcome the limitations of
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traditional optical excitation and thus can further developed. The first optical recording of neuronal activity
improve the tissue penetration of both fluorescence im- was achieved by the Hill and Keynes in 1949, in which
aging and neuromodulation. For example, a tissue the light‐scattering changes in active nerves were detec-
penetration of ~5.5 cm has been achieved by ultrasound‐ ted without labeling.[24] Then, a series of label‐free ap-
switchable fluorescence imaging developed by Yao and proaches, including electrochromic optical strategy and
colleagues.[212] For neuromodulation, Hong et al. devel- interferometric optical approaches, have been developed
oped an ultrasound‐mediated light source strategy.[213] to monitor the electrical activities of neurons.[25] How-
For the first time, they realized the local fluorescence ever, these strategies are currently limited to in vitro
emission with ultrasound, thus achieving optogenetic studies. Efforts are needed to further develop suitable
manipulation in the deep brain. Wang and colleagues label‐free in vivo imaging strategies by fully under-
reported a mechanoluminescent material (CaZnOS:Tb), standing the interaction mechanisms between cell elec-
which can produce light emission at 544 nm by a rotating trophysiological changes and light. For neuromodulation,
magnetic field and active optogenetic proteins.[214] In an ultrafast NIR laser (~700 nm)‐based label‐free strategy
addition, chemiluminescence and bioluminescence can has just been developed to control the store‐operated
also be used as internal excitation sources to get rid of the calcium channels and thus neuronal activity.[178] And
limitations brought about by external light excitation. Shu and Bo groups developed a label‐free midinfrared
More recently, Gao and colleagues developed a self‐ neuromodulation approach to reversibly control the
illuminating NIR‐II bioluminescence imaging strategy neuronal signaling and behavior in vivo by controlling
by the bioluminescence resonance energy transfer be- the voltage‐gated K+ channel, which showing highly
tween NanoLuc luciferase and NIR‐II Ag2S QDs, which promising for clinical application.[179] Exploring the
showed higher signal‐to‐noise ratios and tissue penetra- interaction mechanism between endogenous molecules
tion depth than the conventional fluorescence imaging of neural cells and light of different frequencies, wave-
modality.[215] These activable strategies show great po- lengths and densities will provide broad prospects for the
tential to improve the tissue penetration depth of optical development of label‐free neuromodulation technologies
strategies. Further understanding the energy transfer in the future. The in‐depth exploration of the interaction
process and mechanism between probe pairs by adjusting mechanism of biomolecules and light in these label‐free
the energy‐level matching and distance of probe pairs will neuroimaging and neuromodulation technologies will
help to design probes with higher luminous efficiency to help us to further improve the accuracy and cell speci-
achieve higher tissue penetration depth imaging and ficity of label‐free optical techniques.
manipulation in the future.
4.3 | Multi‐channel
4.2 | The safety
The brain is a highly complex electrochemical computing
Current NIR neuroimaging and neuromodulation machine with a huge number of neural cells and their
methods usually require endogenous or exogenous probe synaptic connections, whose function is involved in
labeling. The biocompatibility of the probe is the pre- multiple processes of numerous types of cells, including
requisite to its biomedical application and further clinical the neural signaling ion transport, membrane potential
translation due to the highly sensitive of neural systems. transmission, neurotransmitter exchange, as well as the
The in‐depth mechanisms of the interactions between the dynamic changes of other brain‐related physiological and
probe and brain tissue as well as the potential toxicity of pathological molecules. Fully understanding the mecha-
the probe are still lacking in systematic research and nisms of how the brain works requires full monitoring of
evaluation. Especially for the recent emerging NIR‐II the multiple processes of the brain. Multichannel optical
optical techniques, how to obtain highly biocompatible approaches offer the possibility of real‐time monitoring
NIR‐II probes still faces great challenges. Thus, further the dynamic physiological characteristics of different
efforts should be paid to make sure that the probes are types of neural cells by light signals at different wave-
free of toxic elements, can cross the BBB efficiently, and lengths or lifetimes.[43,216] Recently, Pieribone and col-
are easily metabolized or biodegradable to ensure that leagues developed a dual‐polarity voltage imaging
they meet the needs of future clinical applications. approach for multi‐channel brain imaging. In this study,
Another promising strategy to address the safety of the neural activities of multiple neuron types were suc-
optical technologies is to develop label‐free NIR imaging cessfully monitored in vivo by several voltage sensors
and manipulation methods. For neuroimaging, several (Ace‐mNeon2, VARNAM2, pAce and pAceR).[217]
label‐free optical electrophysiology techniques have been Although such important progresses have been achieved,
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the current multi‐channel imaging is still far from 4.4 | Future clinical applications
meeting the needs of brain science research. Further ef-
forts may be paid on both the probes and imaging in- While NIR neuroimaging and neuromodulation methods
strument. For the probe, it is necessary to develop NIR have been widely used in in vitro and small animal
probes with high cell‐specificity, high sensitivity, high research, their clinical applications are still facing chal-
biocompatibility, and narrow emission peaks at different lenges. This is primarily due to the limited depth of tissue
emission wavelengths to meet the needs of different penetration of light. With the integration and development
neural signal monitoring. On the other hand, high of interdisciplinary technologies such as devices and data
spatiotemporal resolution imaging equipment capable of computing, the NIR approach has achieved preliminary
simultaneously collecting neural signals in different op- clinical applications, and it is expected to achieve break-
tical bands is also needed for brain function research. throughs in clinical applications in the following directions
Recently, Wang's group has developed wide‐spectrum in in the future. First, fNIRS is currently the most successful
vivo and microscopic imaging systems, which can meet NIR approach for imaging brain functions in clinical
the multi‐channel real‐time imaging at the wide range of practice.[224] With advancements in equipment, data
400–1700 nm, which is expected to provide a powerful computing methods, and integration with other brain
imaging platform for future multi‐channel brain functional imaging modes, it is expected to improve the
imaging.[218,219] accuracy of fNIRS signal acquisition and the correlation
Multichannel optical approaches are also critical for between signals and cognitive behaviors of humans. This
neuromodulation since the control of neural activity is will further promote its clinical application in the future.
highly complex in the brain. Generally, different neurons Second, the integration of optogenetics and microelectrode
in the brain perform different functions such as excit- technologies has promising applications in the field of
atory and inhibitory. In a single neuron, its neural ac- multifunctional neural monitoring and modula-
tivity is controlled by different ion channels, thus tion.[225,226] Currently, minimally invasive implanted
achieving depolarization (activation), polarization (inhi- microelectrodes‐based brain‐computer interface technol-
bition) and downstream sequential neural activity of ogy is being tested in clinical trials. The use of minimally
neural cells. Thus, precise neuromodulation also requires invasive implantation techniques can effectively prevent
precise multi‐channel optical technology. Optogenetic the attenuation of light signals caused by the skull,
technology in the visible window using light‐sensitive ion enabling imaging and modulation in deep brain regions.
channels, such as Archaerhodopsin (Arch),[220] Chan- As a result, the integration of NIR technology and micro-
nelrhodopsin (ChR),[221] and Halorhodopsin (NpHR),[222] electrode technology is anticipated to advance the appli-
has made it possible to manipulate different activities of cation of the NIR approach in the field of brain‐computer
cells using light with different wavelengths. In the future, interfaces. Third, the eye is an optically transparent organ
interdisciplinary research based on endogenous NIR that is closely connected with the central nervous system,
light‐responsive molecules, exogenous NIR light‐ and its function can reflect and affect the function of the
responsive probes, and multi‐channel optical manipula- central nervous system. For example, optical coherence
tion devices will hopefully promote the development of tomography using the NIR light source is extensively used
next‐generation wireless multi‐channel neural manipu- in clinical practice, and has been explored for the detection
lation technologies. of neurodegenerative diseases such as AD.[227] In addition,
Another critical direction of the multichannel optical the use of light to regulate the eye nerves can also indirectly
approaches is the combination of neuroimaging and regulate the activity of the central nervous system. The
neuromodulation techniques for simultaneous moni- regulation of specific neurons in the hypothalamus or
toring and modulation of neural functions in vivo. cortex has been realized through the light excitation of the
Currently, a dual‐functional optical strategy has been optic nerve, thereby realizing the light regulation of blood
achieved in the visible windows. For example, Cohen's sugar metabolism and animal behavior.[228,229] With the
group combined photogenetic neuromodulation with further understanding of the relationship between ocular
voltage imaging technique in one system to reveal hidden function and central nervous system function, transocular
principles of neural circuit function in vivo.[223] After NIR neuroimaging and modulation technology is expected
solving the above‐mentioned basic problems of multi‐ to be applied clinically in the future.
channel NIR neuroimaging and neuromodulation, it is
believed that the combined multifunctional optical tech- A C KNO W L E D G E ME N T S
nology will play an increasingly important role in This work was supported by the National Key Research
neuroscience research in the near future. and Development Program (2021YFF0701804), the
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210. Y. Liu, H. Hong, J. Xue, J. Luo, Q. Liu, X. Chen, Y. Pan, J. Zhou, AUTHOR BIOGRAPHIES
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211. J. Yuan, H. Liu, H. Zhang, T. Wang, Q. Zheng, Z. Li, Adv.
Hongqiang Yin received his Ph.D. from
Mater. 2022, 34, 2108435.
Nankai University in 2020. Now he con-
212. T. Yao, Y. Liu, L. Ren, B. Yuan, Quant. Imaging Med. Surg.
2021, 11, 957. ducts his postdoctoral studies in Suzhou
213. X. Wu, X. Zhu, P. Chong, J. Liu, L. N. Andre, K. S. Ong, K. Institute of Nano‐Tech and Nano‐Bionics
Brinson, Jr, A. I. Mahdi, J. Li, L. E. Fenno, H. Wang, G. Hong, (SINANO), Chinese Academy of Sci-
Proc. Natl. Acad. Sci. 2019, 116, 26332. ences. His current research focus on neuroimaging
214. Y. Zhang, X. Zhang, H. Wang, Y. Tian, H. Pan, L. Zhang, F. and neuromodulation in the NIR‐II window.
Wang, J. Chang, Adv. Funct. Mater. 2021, 31, 2006357.
215. M. J. Afshari, C. Li, J. Zeng, J. Cui, S. Wu, M. Gao, ACS Nano
2022, 16, 16824.
Wuqiao Jiang received her Bachelor's
216. Q. Guo, J. Zhou, Q. Feng, R. Lin, H. Gong, Q. Luo, S. Zeng, degree from Chongqing University in
M. Luo, L. Fu, Biomed. Opt Express 2015, 6, 3919. 2021. Now she is studying for a master's
217. M. Kannan, G. Vasan, S. Haziza, C. Huang, R. Chrapkiewicz, degree in Suzhou Institute of Nano‐
J. Luo, J. A. Cardin, M. J. Schnitzer, V. A. Pieribone, Science Tech and Nano‐Bionics (SINANO),
2022, 378, eabm8797. Chinese Academy of Sciences. Her current research
218. D. Huang, S. Lin, Q. Wang, Y. Zhang, C. Li, R. Ji, M. Wang,
focus on optical neuromodulation in the NIR‐II
G. Chen, Q. Wang, Adv. Funct. Mater. 2019, 29, 1806546.
window.
219. G. Chen, S. Lin, D. Huang, Y. Zhang, C. Li, M. Wang, Q.
Wang, Small 2018, 14, 1702679.
220. M. El‐Gaby, Y. Zhang, K. Wolf, C. J. Schwiening, O. Paulsen, Yongyang Liu received his Bachelor's
O. A. Shipton, Cell Rep. 2016, 16, 2259. degree from Shanxi Agricultural Uni-
221. G. Nagel, T. Szellas, W. Huhn, S. Kateriya, N. Adeishvili, P. versity in 2018. He is currently pursuing
Berthold, D. Ollig, P. Hegemann, E. Bamberg, Proc. Natl.
his Ph.D. under the supervision of Prof.
Acad. Sci. U. S. A. 2003, 100, 13940.
Qiangbin Wang and Guangcun Chen at
222. H. Feroz, B. Ferlez, C. Lefoulon, T. Ren, C. S. Baker, J. P.
Gajewski, D. J. Lugar, S. B. Gaudana, P. J. Butler, J. Hühn, M. Suzhou Institute of Nano‐Tech and
Lamping, W. J. Parak, J. M. Hibberd, C. A. Kerfeld, N. Smirnoff, Nano‐Bionics, Chinese Academy of Sciences. His
M. R. Blatt, J. H. Golbeck, M. Kumar, Biophys. J. 2018, 115, 353. research interests focus on NIR voltage‐sensitive in-
223. L. Z. Fan, S. Kheifets, U. L. Böhm, H. Wu, K. D. Piatkevich, dicators for membrane potential imaging.
M. E. Xie, V. Parot, Y. Ha, K. E. Evans, E. S. Boyden, A. E.
Takesian, A. E. Cohen, Cell 2020, 180, 521.
Dongyang Zhang graduated from Hefei
224. P. Pinti, I. Tachtsidis, A. Hamilton, J. Hirsch, C. Aichelburg,
S. Gilbert, P. W. Burgess, Ann. N. Y. Acad. Sci. 2020, 1464, 5.
University of Technology in 2021. Now
225. S. Park, Y. Guo, X. Jia, H. K. Choe, B. Grena, J. Kang, J. Park, he is pursuing for a master's degree at the
C. Lu, A. Canales, R. Chen, Y. S. Yim, G. B. Choi, Y. Fink, P. Suzhou Institute of Nanotechnology and
Anikeeva, Nat. Neurosci. 2017, 20, 612. Nanobionics, Chinese Academy of Sci-
226. L. Zou, H. Tian, S. Guan, J. Ding, L. Gao, J. Wang, Y. Fang, ences. His current research focuses on the develop-
Nat. Commun. 2021, 12, 5871. ment of near‐infrared fluorescent calcium ion
227. X. Hadoux, F. Hui, J. K. Lim, C. L. Masters, A. Pébay, S.
indicators.
Chevalier, J. Ha, S. Loi, C. J. Fowler, C. Rowe, V. L. Ville-
magne, E. N. Taylor, C. Fluke, J. P. Soucy, F. Lesage, J. P.
Sylvestre, P. Rosa‐Neto, S. Mathotaarachchi, S. Gauthier, Z. S. Feng wu received his BSc degree from
Nasreddine, J. D. Arbour, M. A. Rhéaume, S. Beaulieu, M. Soochow University in 2019. Then, he
Dirani, C. T. O. Nguyen, B. V. Bui, R. Williamson, J. G. joined Suzhou Institute of Nano‐Tech
Crowston, P. van Wijngaarden, Nat. Commun. 2019, 10, 4227. and Nano‐Bionics (SINANO) as a
228. D. Nelidova, R. K. Morikawa, C. S. Cowan, Z. Raics, D. research assistant. He is currently pur-
Goldblum, H. P. Scholl, T. Szikra, A. Szabo, D. Hillier, B.
suing his Ph.D. under the supervision of Prof.
Roska, Science 2020, 368, 1108.
229. J.‐J. Meng, J.‐W. Shen, G. Li, C.‐J. Ouyang, J.‐X. Hu, Z.‐S. Li,
Qiangbin Wang at SINANO. His research interests
H. Zhao, Y.‐M. Shi, M. Zhang, R. Liu, J. T. Chen, Y. Q. Ma, T. focus on NIR‐II imaging systems.
Xue, Cell 2023, 186, 398.
YIN ET AL.
- 31 of 31
Yejun Zhang is an Associate Professor Chinese Academy of Sciences. His research interest
in Suzhou Institute of Nano‐Tech and focuses on the NIR‐II fluorescence imaging technol-
Nano‐Bionics (SINANO), Chinese Acad- ogies for biomedical applications in regenerative
emy of Sciences. He joined SINANO as a medicine and neuroscience.
research assistant in July 2011. He got his
Ph.D. from University of Science and Technology of Qiangbin Wang is a full Professor in
China in 2021 and was promoted to Associate Pro- Suzhou Institute of Nano‐Tech and
fessor in the same year. His research interest focuses Nano‐Bionics (SINANO), Chinese Acad-
on the development of NIR‐II fluorescence probes. emy of Sciences. He got his Ph.D. from
East China University of Science and
Chunyan Li is a Professor in the Suzhou Technology in 2002. He worked as a Postdoc Associate
Institute of Nano‐Tech and Nano‐Bionics and later as an Assistant Research Professor at Ari-
(SINANO), Chinese Academy of Sci- zona State University from 2004 to 2008. In July 2008,
ences. He received his Ph.D. degree from he joined SINANO as a Professor focusing on
Fudan University in 2012. He subse- controlled synthesis of inorganic semiconductor
quently joined SINANO as an Assistant Professor in nanocrystals and their bioapplications in cancer
July 2012 and was promoted to Associate Professor in theranostics, regenerative medicine and neuroscience.
2015, Professor in 2019. His research interests involve He is now the Deputy Director of SINANO and the
NIR‐II and multifunctional nanomaterials for sensing, Director of Key Laboratory of Nano‐Bio Interface of
bioimaging, and drug delivery. Chinese Academy of Sciences.
Guangcun Chen is a full Professor in

Suzhou Institute of Nano‐Tech and
Nano‐Bionics (SINANO), Chinese Acad-
emy of Sciences. He got his Ph.D. from
Zhejiang University in 2011. After that, How to cite this article: H. Yin, W. Jiang, Y. Liu,
He joined SINANO as an Assistant Professor in D. Zhang, F. Wu, Y. Zhang, C. Li, G. Chen, Q.
October 2011. He was promoted to Associate Professor Wang, BMEMat 2023, 1(2), e12023. https://doi.org/
in 2015, then Full Professor in 2021. He is a member 10.1002/bmm2.12023
of Youth Innovation Promotion Association of

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Received: 12 February 2023

Advanced near‐infrared light approaches for

Hongqiang Yin1 | Wuqiao Jiang1,2 | Yongyang Liu1,2 | Dongyang Zhang1,2 |

BMEMat. 2023;1:e12023. onlinelibrary.wiley.com/r/bmemat 1 of 31

1 | INTRODUCTION the programmed change of Na+/K+ channel activity to

Guangcun Chen is a full Professor in

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