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Xanthene-based NIR organic phototheranostics

agents: design strategies and
Cite this: J. Mater. Chem. B, 2025,
13, 2952 biomedical applications
Xiao-Yun Ran, †a Yuan-Feng Wei,†b Yan-Ling Wu,a Li-Rui Dai,c Wen-Li Xia,a
Pei-Zhi Zhouc and Kun Li *a
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Fluorescence imaging and phototherapy in the near-infrared window (NIR, 650–1700 nm) have attracted
great attention for biomedical applications due to their minimal invasiveness, ultra-low photon scattering
and high spatial–temporal precision. Among NIR emitting/absorbing organic dyes, xanthene derivatives
with controllable molecular structures and optical properties, excellent fluorescence quantum yields,
high molar absorption coefficients and remarkable chemical stability have been extensively studied and
explored in the field of biological theranostics. The present study was aimed at providing a comprehen-
sive summary of the progress in the development and design strategies of xanthene derivative fluoro-
phores for advanced biological phototheranostics. This study elucidated several representative
controllable strategies, including electronic programming strategies, extension of conjugated backbones,
and strategic establishment of activatable fluorophores, which enhance the NIR fluorescence of
Received 5th November 2024, xanthene backbones. Subsequently, the development of xanthene nanoplatforms based on NIR fluores-
Accepted 12th January 2025 cence for biological applications was detailed. Overall, this work outlines future efforts and directions for
DOI: 10.1039/d4tb02480j improving NIR xanthene derivatives to meet evolving clinical needs. It is anticipated that this contribution
could provide a viable reference for the strategic design of organic NIR fluorophores, thereby enhancing
rsc.li/materials-b their potential clinical practice in future.

1. Introduction
a
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China. Cancer remains a significant threat to human health, driven by
E-mail: kli@scu.edu.cn the rapid proliferation, systemic dissemination, and metastasis
b
Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West
of malignant cells. Early detection is crucial for improving
China Hospital, Sichuan University, Chengdu 610041, China
c
Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu,
treatment outcomes as it significantly increases the chances
Sichuan, China of successful intervention. Over the past several decades, med-
† These authors contributed equally to the work. ical imaging technologies have become central to cancer

Xiao-Yun Ran was born in Yuan-Feng Wei obtained his M.D.

Guizhou Province, China. He in oncology at West China Hospital,
obtained his Master’s degree in Sichuan University in 2023.
2021 and has since been pursuing Currently, he is working as a post-
his PhD at the College of doctor. His research interests focus
Chemistry, Sichuan University. on nanomedicine, photodynamic/
His research interests are photothermal therapy and
focused on the development of immunotherapy.
organic molecule-based photo-
theranostic agents.

Xiao-Yun Ran Yuan-Feng Wei

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diagnosis, such as magnetic resonance imaging (MRI),1,2 X-

rays,3 positron emission tomography (PET),4–6 computed tomo-
graphy (CT),7–9 and ultrasound imaging.10,11 Despite their
widespread adoption, these technologies face inherent limita-
tions, including radioactivity, low sensitivity, high costs, and
inadequate spatial–temporal resolution, which hinder their
utility for real-time guidance during surgical and therapeutic
procedures.
At the same time, conventional cancer treatments, such as
radiotherapy, chemotherapy, targeted therapy, immunother-
apy, and surgical resection, often suffer from issues related to Scheme 1 Schematic of the light penetration depth and light propagation
suboptimal efficacy and severe side effects.1,12,13 These chal- in biological tissue.
lenges have driven the search for more effective, targeted, and
personalized treatment strategies. The emergence of precision
medicine presents an exciting opportunity to address these properties, ease of chemical modification, biocompatibility,
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limitations by combining diagnostic and therapeutic functions stability, and cost-effectiveness. Consequently, they have
in a single, unified platform, thus maximizing therapeutic emerged as key players in NIR phototherapy and diagnostic
outcomes while overcoming the drawbacks of isolated diagnos- applications. These dyes can be broadly categorized into four
tic or treatment modalities.14,15 Among the most promising main classes based on their molecular structures, namely,
solutions are phototheranostic strategies, which integrate diag- polymethine cyanines,40–42 BODIPY dyes,43–45 BBTD-based
nostic imaging (e.g., photoacoustic imaging and fluorescence donor–acceptor oligomers (D–A–D or A–D–A),46,47 and J-
imaging) with therapeutic approaches (e.g., photodynamic aggregates.48 Each of these classes offers distinct advantages,
therapy (PDT) and photothermal therapy (PTT)) to deliver including strong fluorescence, high photostability, and syn-
precise diagnostics and localized treatments, thereby minimiz- thetic flexibility, making them highly versatile. By modifying
ing toxicity and aligning with the principles of precision their structures, these fluorophores can achieve enhanced
oncology.16–23 fluorescence intensities, optimized photothermal properties,
Recent advancements in near-infrared (NIR, 650–1700 nm) and improved photodynamic activity, all of which are crucial
imaging and therapy systems have transitioned from theoreti- for their effectiveness in NIR phototherapy (Scheme 1).20,41,49–56
cal concepts to clinical applications.24–30 NIR fluorophores, Despite their advantages, as small-molecule dyes, xanthene-
ranging from single-walled carbon nanotubes (SWNTs),26,31 based dyes face challenges when compared to traditional NIR
quantum dots,32–34 and lanthanide nanoparticles35–37 to dyes, such as cyanine, semi-cyanine, BODIPY, and squaraine.
organic small-molecule dyes,38–40 have shown tremendous Their relatively short excitation and emission wavelengths limit
potential in biomedical applications, particularly in fluores- their use in in vivo imaging and phototherapy. Nevertheless,
cence imaging and phototherapy. These innovations have xanthene dyes offer significant promise owing to their multiple
paved the way for the integration of NIR-based phototherapeu- functionalization sites, which allow for modifications that can
tic and diagnostic strategies. Small-molecule NIR dyes are extend their absorption into the NIR region. This ability to
particularly appealing due to their tunable photophysical extend absorption into the NIR spectrum makes xanthene dyes

Prof. Pei-Zhi Zhou received his Prof. Li Kun received his PhD at
M.D. in Clinical medicine from Sichuan University in 2008. He
Sichuan University in 2013 and then conducted postdoctoral
finished his neuroanatomical research at the University of
research fellowship program at Hong Kong in 2010–2011. Cur-
University of Pittsburgh in 2018. rently, he is a Professor at the
He currently works as an College of Chemistry, Sichuan
Associate Professor at the University, where he also serves
Department of Neurosurgery of as a Doctoral Supervisor. His
West China Hospital. He research mainly focuses on the
completes about 300 tumor design and application of fluores-
surgeries every year. He is also cent dyes for cell imaging and
Pei-Zhi Zhou focused on basic and Kun Li fluorescence-guided surgery.
translational research, mainly
on tumor microenvironment and gene-targeted therapy for central
nervous system and tumor therapy.

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some of the most promising photosensitizers for NIR-based fluorescent dyes.1 This discovery laid the foundation for the
applications.38,41,57 Despite considerable progress in the synth- development of fluorescein- and rhodamine-based dyes, such
esis and functionalization of xanthene derivatives and numer- as Rhodamine 123,58 which have become indispensable tools in
ous reviews addressing their biological applications in imaging chemical, biological, and medical research.42,59 These dyes are
and detection, there is a noticeable gap in the literature highly valued for their high sensitivity, real-time detection, and
regarding the design and synthesis of NIR xanthene derivatives non-destructive analysis.60,61 Their structural flexibility, com-
as well as strategies to enhance their therapeutic and diagnostic bined with water solubility, stability, and brightness, makes
capabilities. This gap is critical as these aspects are essential for them particularly effective in fluorescence imaging applica-
developing high-performance xanthene photosensitizers cap- tions, allowing researchers to visualize and quantify various
able of meeting the demands of modern cancer theranostics. biological processes with great precision.62–64
This review aims to address this gap by providing a compre- However, the fluorescence emission of xanthene-based
hensive discussion on the core structure of traditional xanthene dyes typically falls within the visible spectrum, which limits
derivatives and the key strategies used to extend their absorp- their applications in deep tissue imaging and in vivo
tion into the NIR region. These strategies include structural studies.24,39,65–67 The fluorescence properties of a fluorophore
modifications, aromatic ring fusion, polymerization, and are primarily determined by the energy gap between the highest
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supramolecular approaches. Furthermore, we will summarize occupied molecular orbital (HOMO) and the lowest unoccupied
the recent advancements in the use of xanthene derivatives for molecular orbital (LUMO). To overcome the limitations of the
fluorescence imaging, PTT, PDT, and theranostics, providing visible spectrum and extend their utility for deep tissue pene-
insights into the design and development of advanced tration, particularly in near-infrared (NIR) applications, several
xanthene-based photosensitizers with enhanced therapeutic strategies have been developed. These included narrowing the
and imaging capabilities. energy gap through extended conjugation, enhancing the rigid-
ity, reducing bond rotation, and improving the fluorescence
yield. Another effective approach was replacing the oxygen
2. Colourful dyes with tenable atom in the xanthene backbone, which red-shifts both the
photophysics absorption and emission wavelengths, thereby making these
dyes more suitable for NIR imaging and therapy (Fig. 1).
In 1871, Adolf von Bayer first synthesized fluorescein by com- While xanthene dyes are widely utilized, their fluorescence
bining phthalic anhydride and resorcinol with zinc chloride, wavelengths typically lie within the visible range, which limits
marking a significant breakthrough in the development of their application in deep tissue imaging and in vivo diagnostics.

Fig. 1 Development of the chemical structure of xanthene-based dyes in recent years.

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To overcome this limitation, numerous strategies have been

employed to extend the absorption and emission wavelengths
of xanthene derivatives into the NIR region (650–1700 nm),
where tissue penetration is optimal for biomedical applica-
tions. These strategies include modifications at the 9-position
and 10-position of the xanthene core and conjugation exten-
sion, each of which plays a critical role in enhancing the optical
properties of the dyes. This section explores the various struc-
tural modifications of xanthene dyes to optimize their proper-
ties for phototheranostic applications, which combine both
diagnostic and therapeutic functions in a single platform.
The section is divided into three subsections, each discussing
key strategies for modifying the xanthene structure to enhance
its optical properties and biological applications.
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2.1. 9-Position modification

Fig. 2 Amino modification at the 9-position.
The 9-position of xanthene dyes plays a pivotal role in altering
the photophysical and biological properties. Modifications at
this position have a significant impact on fluorescence emis-
sion, solubility, and biological targeting, all of which are crucial the potential of amino-modified xanthene dyes for biomedical
for their application in imaging and therapeutics. This section applications.
explores the key strategies for 9-position modification, includ- 2.1.2. Carbon modification. Carbon-based modifications
ing amino, carbon-based, and alternative group modifications. at the 9-position are another popular strategy to improve the
2.1.1. Amino modification. One of the most studied mod- fluorescence properties and NIR absorption of xanthene dyes.
ifications at the 9-position is the introduction of amino groups, By introducing alkenyl, alkynyl, or alkyl groups, the electronic
which significantly enhance the fluorescence properties and properties of the dyes can be modified, which results in
solubility of dyes. The introduction of amino groups allows for extended absorption and emission wavelengths.
further functionalization, making the dyes more versatile in In 2017, Guo et al. developed a lysosome-targeting probe (F3-
biological applications. 1) based on an alkene-Si-xanthene scaffold.73 This probe exhib-
In 2008, Wu and Burgess reported a novel synthesis route for ited longer absorption and emission wavelengths compared to
amino-xanthene fluorophores.68 They started with ditriflyl amino-modified xanthene derivatives, making it more suitable
xanthone and treated it with piperidine derivatives to produce for detecting reactive oxygen species (ROS) in lysosomal cell
a diamine intermediate. This intermediate was then triflated death studies. The carbon-based modification not only
and reacted with appropriate amines to yield a variety of amino- extended the fluorescence range but also enhanced the
modified xanthene derivatives. The resulting compounds signal-to-noise ratio for more accurate imaging.
exhibited green fluorescence, with the absorption maxima Following this approach, Frei et al. (2019) synthesized a
ranging from 456 to 499 nm and emission maxima between photoactivatable fluorophore (F3-2a), which was initially non-
537 and 562 nm. Notably, the Stokes shift of these compounds fluorescent but converted into a red-emitting photoproduct (F3-
ranged from 59 nm to 82 nm, which was significantly larger 2c) upon UV irradiation.64 The emission wavelength of 670 nm
than that of previous rhodamine derivatives, thus enhancing allowed for controlled fluorescence activation in biological
their signal-to-noise ratio in cell imaging (Fig. 2, F2-1-3).69 systems, making it ideal for dynamic imaging and therapeutic
Further work by the Klan group in 2015 introduced acyl- monitoring.
amino and sulfonamide groups at the 9-position of Si In addition, alkynyl-xanthene derivatives exhibit bathochro-
Rhodamine.70 These modifications led to Stokes shifts as large mic shifts due to the electron-withdrawing properties of the
as 210 nm for amido-Rhodamine (F2-4) and 173 nm for carbon–carbon triple bond. These derivatives also exhibit
sulfamide-Rhodamine (F2-5), significantly improving the higher quantum yields as the coplanarity between the
fluorescence properties and biological targeting capabilities triple bond and the fluorophore facilitates electron delocaliza-
of the dyes. These lysosomal-targeting dyes exhibited excellent tion. For example, in 2014, Pastierik et al., developed
photostability and high pH stability, making them ideal for mitochondria-targeted fluorescent dyes (F3-3a, b) based on 9-
lysosomal imaging and pH sensing applications. phenylethynylpyronine scaffolds, which exhibited redshifted
In 2017, Hell’s research group developed a series of amino-x emissions at 708 nm and 738 nm.74 Notably, Wei et al. reported
Rhodamine derivatives by introducing secondary amino groups various novel dyes utilizing the rational design strategy by
at the 9-position of heteroatom-substituted Rhodamine (Fig. 2, replacing the 9-position with other groups based on xanthene
F2-6-9).71,72 The resulting dyes exhibited large Stokes shifts, all skeleton, which was conjugated to the triple bonds and
exceeding 135 nm, and showed excellent lysosomal targeting employed to visualize DNA replication and protein synthesis
and cellular imaging abilities. This series further demonstrated activity via 16-color imaging (F3-4).75

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Fig. 4 Thiol modification at the 9-position.

converted into fluorescent derivatives (F4-2a), which enabled

the selective detection of cancerous tissues. Zhang et al.89
reported oxygenpyronine (F4-3), which discriminated between
cancerous and normal cells. The free probe F4-3 displayed weak
Fig. 3 Carbon modification at the 9-position.
fluorescence regardless of excitation at 450 or 580 nm but
showed distinct emission at 570 nm under 520 nm excitation.
Xanthone exhibited strong electronic-donor capability and Upon the addition of Cys and GSH, F4-3 converted into ami-
rigid conjunction skeleton, which has been developed for nopyronine F4-3a and thiolpyronine F4-3b, emitting at 545 nm
constructing fluorescence dyes by extending the p- and 622 nm, respectively. When incubated in cancer cells,
conjugation. Li’s group modified the xanthene-based fluoro- probe F4-3 exhibited bright green and red fluorescence through
phore by incorporating a carbon atom at the 9-position, which distinct channels (Fig. 4).
resulted in significant bathochromic shifts. The donor–accep- 9-Position-substituted xanthene-based probes possess sev-
tor (D–A) interaction, reorganization energy, and intersystem eral intrinsic advantages, including high wavelength tunability
crossing (ISC) were optimized to achieve high photothermal (ranging from the green to the near-infrared (NIR) region), a
conversion efficiency (PCE) and reactive oxygen species (ROS) large Stokes shift, and remarkable photostability.79,87,90 Due to
generation, ultimately enhancing the antitumor efficacy (F3-5- these properties, the modification of xanthene-based probes at
7) (Fig. 3).20,76–78 the 9-position successfully addressed many of the limitations
2.1.3. Alternative group modifications. In addition to associated with classical fluorophores, making them an excep-
amino and carbon-based substitutions, alternative functional tionally powerful platform for designing phototheranostic
groups such as thiol, oxygen, and sulfur can be introduced at agents. Additionally, incorporating diverse functional groups
the 9-position to enhance the biothiol responsiveness and allows these probes to detect a variety of targets, such as nitric
selectivity of the dyes for specific biological targets. These oxide (NO),91 peroxynitrite,92 glutathione (GSH),87 pH,93 and
modifications are valuable for designing highly specific fluor- viscosity.94
escent probes for use in diagnostic imaging and therapeutic
applications.42,79–86 2.2. 10-Position modification
For instance, in 2015, Liu et al., developed thiolpyronine (F4- 2.2.1. Heteroatom substitution. The primary chromophore
1), which could discriminate between cysteine (Cys), homocys- of fluorescein and rhodamine is the xanthene core, which
teine (Hcy), and glutathione (GSH) based on the direct con- contains a bridging oxygen atom at the 10-position. While this
jugation of a thiol group with the xanthene fluorophore.87 The atom stabilizes the structure and maximizes p-conjugation, its
probe exhibited no fluorescence in its free form, but fluores- ability to red-shift the emission wavelength is limited. Recent
cence was restored upon exposure to thiol-containing com- developments in NIR xanthene derivatives have explored95–97
pounds, demonstrating its biothiol-responsive imaging heteroatom substitution at the 10-position (C 0 10) as a strategy
capabilities. Similarly, Zhou et al. (2017) developed a ratio- to achieve absorbance in the NIR region. Replacing the brid-
metric probe (F4-2) for ovarian cancer diagnosis based on the ging oxygen atom with elements such as carbon, boron, silicon,
conjugation of GSH and a pyronine moiety.88 The probe dis- phosphorus, selenium, sulfur, phosphine oxide, sulfone, and
played bright red fluorescence at 622 nm in its free form, ketone (CQO) shifts the absorption maxima into the near-
and after interacting with g-glutamyltranspeptidase (GGT), it infrared region, extending both the absorption and emission

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Fig. 5 Carbon atom modification at the 10-position.

wavelengths without significantly affecting the dye’s conju-

gated system.
For instance, in 2001, Drexhage’s group replaced the oxygen
atom with carbon, redshifting the fluorescence emission by
approximately 50 nm (X-2).98 In 2010, Hell, S. W. et al.,
improved the detailed synthesis of a carbopyronin scaffold that
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allows modifications on the final product, i.e., a photostable

dye with large fluorescence quantum yield and the required
absorption and emission bands in the red.99 On the basis of
carbon Rhodamine F5-1, increasing the rigidity of 3 and 6 Fig. 6 Heteroatom modification at the 10-position.
amino substituents or lengthening the p-conjugation system
of its fluorescent parent nucleus could further redshift the
fluorescence emission wavelength (F5-2). In addition, in 2017, promising candidate for long-term biofluorescence imaging.113
Yang’s research group obtained diphenyl carbon Rhodamine In 2017, Cliff I. Stains et al., introduced a borinate functionality
F5-3 by extending the structure of two benzene rings on the into the xanthene scaffold with the goal of leveraging the
carbon Rhodamine parent nucleus, which showed an extremely selective chemical reactivity of this group to afford a ratiometric
long fluorescence emission wavelength, reaching 921 nm sensor for H2O2, and they demonstrated the ability of F6-11 to
(Fig. 5).100 yield robust and tunable ratiometric sensors (Fig. 6).114
Other studies have focused on replacing oxygen with oxygen More recently, heteroatom substitution with a ketone has
group, nitrogen group, and carbon group. In 2004, Detty’s been shown to enhance the photophysical properties of fluor-
group reported Rhodamine dyes in which oxygen was replaced ophores (Fig. 7). In 2022, Schnermann’s group replaced the
by sulfur and arsenic, resulting in redshifts of 24 and 33 nm, oxygen bridge at the 10-position of the xanthene core with an
respectively.101 They also found that replacing O with S, Se, and electron-withdrawing ketone bridge, guided by computational
Te enhanced the intersystem crossing (ISC) process, reducing design. This modification extended the absorbance maximum
the fluorescence quantum yield and promoting singlet oxygen to 860 nm and the emission beyond 1000 nm (F7-1–F7-3).115
production (F6-1-4).102,103 In 2008, Qian’s group synthesized Although the quantum yield remains relatively low and stability
silicon-substituted Rhodamine, achieving a redshift of is limited, the small molecular weight and good solubility offer
90 nm.104 Later, Nagano and co-workers extended this strategy significant opportunities for further exploration. Building on
by replacing oxygen atom with germanium and tin, though Schnermann’s work, Evan W. Miller introduced cyclization to
their emission wavelengths were slightly lower than silicon rigidify the nitrogen, resulting in a more stable and brighter
Rhodamine, similar to carbon-substituted Rhodamine, all of analogue (F7-4).116
which successfully extended the fluorescence emission wave- 2.2.2. Removing the heteroatom. The removal of the brid-
lengths (F6-5-8).105 Next, a series of novel near-infrared (NIR) ging oxygen atom at the 10-position is another powerful strat-
wavelength-excitable fluorescent dyes were prepared by mod- egy to achieve NIR fluorescence. By eliminating the oxygen
ifying the Si-xanthene scaffold to obtain emission in the range atom, the absorption wavelengths can be extended into the
suitable for in vivo imaging, which showed sufficiently high NIR-II region, enabling deep tissue imaging and improving the
quantum efficiency and high tolerance to photobleaching in biological applications of the dyes.
aqueous solution.106–111 In 2015, Wang’s group used phos- Among the various atom replacements in xanthenoid fluoro-
phorus to replace oxygen, where the strong electron- phores, a prominent strategy involves the removal of the
absorbing ‘‘PQO’’ group formed a s*–p* conjugation with
the Rhodamine core, successfully extending the emission
wavelength to over 700 nm (F6-9).112 In 2016, Guo’s research
group synthesized sulfone Rhodamine by replacing oxygen with
a highly electron-absorbing sulfone group. This resulted in
emission wavelengths exceeding 720 nm, surpassing phosphor-
hodamine (F6-10). Additionally, sulfone Rhodamine exhibited
high photostability and cell membrane penetration, making it a Fig. 7 Carbonyl modification at the 10-position.

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Fig. 8 Removal of the heteroatom at the 10-position.

bridging atom. The removal of the bridging oxygen atom

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produces the xanthene fluorophore to achieve absorption

in the near-infrared II (NIR-II) region. For example, in 1954,
the Barker group synthesized a derivative from 3,6-
dimethylaminofluorene, which exhibited long absorption wave- Fig. 9 Extension of the conjugated plane of xanthene.
length up to 955 nm (F8-1).117 In 1991, Akiyama’s group
synthesized the 9-arylene-substituted aminofluorene derivative
(F8-2), exhibiting an absorption wavelength beyond 1052
nm.118 Similarly, in 1999, Wainwright’s group synthesized the which is 45 nm longer than rhodamine B. Subsequently, the
fluorenylrhodamine analogue (F8-3), which also showed an Lavis group synthesized the first V-shaped xanthene dye from
absorption wavelength of 955 nm.119 Although this approach fluoresceins using Pd-catalyzed C–N cross-coupling (F9-2).124 In
has been known for some time, it has only recently garnered 2012, Strongin’s group introduced a naphthalene ring,125
significant attention. Until 2022, Garbacz et al.120 enriched the further shifting the emission to 668 nm and increasing the
xanthenoid dye class by replacing nitrogen with oxygen, creat- Stokes shift to 90 nm. Following this, Zhang et al. reported F9-3,
ing an asymmetric rhodol-like dye (F8-4) and symmetric an efficient NIR dye with a Stokes shift of 73 nm and a
fluorescein-like dyes (F8-5, 6). Building on Garbacz’s work, in fluorescence quantum yield as high as 0.72.126 Building on this
2022, Fan Zhang et al.,121 developed diaminofluorene-based design concept, Xiao’s group replaced aromatic rings with
dyes with molecular weights of 299–504 Da, achieving NIR aliphatic ones to reduce p–p stacking and enhance lipophilicity,
absorption from 700 to 1600 nm, suitable for in vivo NIR all the while preserving the donor–p–acceptor structure. This
bioimaging and sensing applications (F8-7, 8) (Fig. 8). expanded and coplanar conjugation promotes electron deloca-
lization, endowing F9-4 with strong long-wavelength absorp-
tion and emission properties.127
2.3. Extending conjugated plane and chain While extending the absorption and emission wavelengths
The extension of the p-conjugated system is a key strategy to presents certain limitations, combining it with other modifica-
enhance the absorption and emission properties of xanthene- tion strategies can lead to further redshifts. In 2012, Nagano’s
based dyes, especially in the NIR region, where the tissue team developed silicon-based rhodamine dyes with emissions
penetration and biological imaging capabilities are greatly ranging from 660 nm to 740 nm through incremental modifi-
improved. The extension of the conjugated system can be cations (F9-5-7).106 Applying 9-position modifications and
achieved through two main methods: extending the conjugated expanding the p-conjugated system, Yang’s group created a
plane (e.g., by incorporating aromatic rings) and extending the new family of brightly fluorescent dyes (F9-8) with absorption
conjugated chain (e.g., through the introduction of alkynyl or maxima in the deep-NIR spectral region of 800–1000 nm.100,128
other conjugative linkages). These strategies lead to bathochro- Building on this, they reported high-performance NIR-II-active
mic shifts, increased fluorescence quantum yields, and fluorochromic scaffolds, the tetra-benzannulated xanthene
enhanced photostability, all of which are essential for the dyes (F9-9), which absorb at long wavelengths of B1200
application of these dyes in theranostics. nm.129 These dyes demonstrate remarkable resistance to
2.3.1. Extending conjugated plane. The extension of the dipole/H-bonding-induced symmetry breaking, possess struc-
conjugated plane involves the introduction of additional aro- tural rigidity, and exhibit superior photophysical properties
matic rings to the xanthene core (Fig. 9). This modification along with good chemo- and photostability.
effectively increases the conjugation length, which leads to a 2.3.2. Extending conjugated chain (C 0 3- and C 0 6-positions).
redshift in the absorption and emission spectra, making the While extending the p-conjugated plane is effective in red-
dyes suitable for NIR imaging.122 In 2010, Fujita et al. modified shifting the absorption and emission wavelengths, extending
rhodamine B to create F9-1,123 achieving a redshift to 625 nm, the conjugated chain by introducing alkynyl groups or double

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bonds at the C 0 3 and C 0 6 positions can further extend the

absorption into the NIR-II region (1000–1700 nm).
Drawing inspiration from the fluorescence switching
mechanisms of donor–acceptor–donor (D–A–D) dyes such as
CH 1055, techniques such as p-conjugation extension and
donor–acceptor strength adjustment can lead to significant
bathochromic shifts.46 In recent years, Colleen N. Scott’s group
has explored a D–A–D approach to develop far-red to NIR
xanthene-based dyes. They initially coupled pyrrole and indole
at the C-2 position of the xanthene core using the Suzuki–
Miyaura reaction to create dye F10-1,130 which exhibited
absorption and emission wavelengths between 665 nm and
717 nm. By introducing indolizine at the C-3 position via C–H
activation, the absorption maxima were shifted to the NIR-II
region (900–1100 nm) for dye F10-2.131 This extension of the
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conjugation system significantly enhanced the NIR fluores-

cence, and the dyes demonstrated excellent biological imaging
capabilities.
Further modifications incorporated a thiophene spacer
between the xanthene acceptor and amine donors, enhancing
the donor strength and further extending the conjugation. This
led to the development of two types of dyes: a thienylpiperidine
donor (F10-3)132 and a series of thienyldibenzazepine donors
(F10-4).91 These dyes exhibited absorption and emission max-
ima in the NIR-II region (890–1260 nm), and F10-4 was success- Fig. 10 Extension of the conjugated chain C 0 3- and C 0 6-positions of
fully used in a nano-receptor to detect nitric oxide (NO) in a xanthene.

mouse liver model. Jared H. Delcamp also contributed to the

development of NIR-II fluorescent dyes by tuning indolizine 3. Biomedical applications
donors with N,N-dimethylaniline (DMA) groups. His group
synthesized FluIndz dyes (F10-5, 8),133–135 which exhibited Xanthene-based functional dyes have been widely used in life
absorption in the NIR-IIa and NIR-IIb regions and demon- science and materials science.140–142 Numerous studies have
strated ‘‘cyanine-like’’ behavior in CS2. These dyes had absorp- reviewed their functions in the field of materials science.
tion ranging from 1590 to 2088 nm (F10-9), opening up new Meanwhile, due to their excellent photophysical properties
possibilities for deep-tissue imaging.136 such as high fluorescence quantum yield, high molar extinction
Additionally, substituting silicon for oxygen in the xanthene coefficients, good chemical stability, excellent photostability
core has been shown to induce bathochromic shifts of approxi- and easily modifiable backbones, they have been widely applied
mately 90 nm.104 Ellen M. Sletten’s group investigated the in the biomedical field.143,144 Previously, Oriola AO et al.
combination of silicon-substituted xanthene with DMA- reviewed their biological implications in antifungal, antibacter-
decorated indolizine donors to achieve longer absorption and ial, coagulant, antioxidant, anti-inflammatory, and insecticidal
emission wavelengths. This approach produced small-molecule effects.145 Silva CFM et al. summarized xanthene as a core
organic fluorophores, with the emission extending over 300 nm structure for the development of antileishmanial agents.146
beyond current capabilities and entering the NIR-II region.137 Maia M et al. overviewed the design strategies and biological
While indolizine has facilitated longer wavelength shifts com- activities of xanthene in medicinal chemistry.147 In recent
pared to DMA, it remains unclear whether this is due to years, xanthene derivatives have been extensively studied and
extended conjugation or increased donor strength from better explored in the field of fluorescence bioimaging, biosensing
overlap with the planar nitrogen atom. To distinguish these and light-mediated therapy including phototherapy (PTT) and
effects, vinyl aniline, which has a similar number of p-bonds photodynamic therapy (PDT). For example, Dai M et al. pre-
and nitrogen donor electrons as indolizine, was appended as a sented an overview of strategies applied toward tuning the
donor. Recently, Huimin Ma et al. utilized xanthene to create emission bathochromic shift to xanthene fluorophores and
the dye F10-6, which emits in the NIR-II range (720–1260 briefly exemplified its applications in bioimaging.148 Samanta
nm).138 Similarly, Jared H. Delcamp’s group used DMA with S et al. overviewed recent trends in the development of con-
silicon-substituted xanthene to develop NIR and NIR-II emit- temporary super-resolution bioimaging strategies using com-
ting materials (F10-7),139 comparing the photophysical proper- mon fluorophores including xanthene.149 Si D et al. reviewed
ties of donor groups on a consistent Si-substituted xanthene- the mechanism and design strategies of xanthene derivatives
based core with varied structures and conjugation lengths rhodamines and their applications in bioimaging and
(Fig. 10). biosensing.150,151 Briefly, xanthene-based functional dyes have

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been used in bioimaging for some fields, but little has been strategies, making their excitation and emission wavelengths
summarized in cancer imaging and light-mediated PTT/PDT, as reach the near-infrared region, which is more suitable for
well as vascular imaging and neuroimaging; we will highlight in bioimaging. Furthermore, spiro modifications173–175 could
this review. modulate the pKa of the molecule, making it more suitable
FLI and phototherapy has been widely utilized in the diag- for response imaging in various pH organismal environments.
nosis and treatment of solid tumors, skin diseases, and other Urano et al. designed and synthesized a novel near-infrared
diseases owing to its non-invasive detection, high spatiotem- fluorescent probe, FolateSiR-1,176 utilizing a Si-rhodamine
poral resolution, easy operation, and real-time monitoring. To fluorophore with a carboxy group at the benzene moiety. This
accomplish high-performance diagnosis, the fluorescence probe is coupled to a folate ligand through a negatively charged
probes should have good biocompatibility, large extinction tripeptide linker, resulting in very low background fluorescence
coefficient in the NIR region, and specific tumor and an SNR of up to 83 in folate receptor-expressing tumor-
targeting.152,153 Several PSs such as indocyanine green and bearing mice within 30 minutes, allowing for precise tumor
methylene blue have been approved by the U.S. Food and Drug imaging (Fig. 11). Kanduluru et al.177 established strong bind-
Administration for clinical use and have been utilized for ing and specificity of the NK1R-targeted ligand using a rhoda-
fluorescence-guided tumour resection during clinical surgery mine conjugate, leading to the development of the NIR dye
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and therapy.154 Xanthene-based dyes have the advantages of conjugate NK1RL-Peptide-LS288, which accurately images can-
strong absorption, excellent biocompatibility, and tunable cer and guides surgical removal in an NK1R-transfected
optical properties. Thus, they are extremely popular in imaging HEK293 tumor xenograft model.
and therapy. In 2020, Wang et al.178 developed an activatable two-photon
NIR fluorescent probe, DHQ-Rd-PN (Fig. 12a). This probe
3.1. FLI exhibited increased NIR emission in response to peroxynitrite,
FLI in the visible spectrum (400–650 nm) faces a constraint in facilitating the detection of ONOO in both cells and in vivo.
terms of penetration depth due to light–tissue interactions.155 Moreover, it enabled the imaging of ONOO production in
These interactions include substantial photon scattering, xenograft 4T1 tumor-bearing mice. In 2023, Jiang et al.179
photon absorption, and the presence of tissue autofluores- modified a rhodamine dye, observing different uptake and
cence. Consequently, there is an urgent requirement for retention times across various cell types. Notably, cancer cells
advancements in the field of deep tissue penetration and demonstrated greater uptake through active transport, allowing
in vivo fluorescence imaging. The near-infrared spectrum is for prolonged retention of the fluorescent moiety, which
further categorized into two distinct channels: NIR-I (650– enabled long-term tumor-specific imaging. They designed the
950 nm) and NIR-II (1000–1700 nm).21,24,35,156,157 While NIR-I probe NYL2-NQO1 to detect human nicotinamide adenine
fluorescence imaging is extensively used in both basic research dinucleotide (phosphate) reduced (NAD(P)H): quinone oxido-
and clinical applications, it also has some limitations. This reductase isozyme 1 (hNQO1), showing a higher signal contrast
method permits the observation of intricate biological pro- between cancerous and normal cells than its predecessor
cesses only within a shallow depth region of about 0.2 mm, (Fig. 12b). Upon intravenous injection into A549-bearing nude
even though it provides micron-level spatial resolution.31,158 mice, the tumor area was illuminated within two hours, reveal-
Recent research has showed the advantages of optical bioima- ing fluorescent signals 3.1-fold and 6.9-fold stronger than those
ging within the NIR-II channel, which offers reduced tissue in skin and muscle tissues, respectively. These results suggest
autofluorescence and signal attenuation. This translates into a that NYL2-NQO1 could be an effective tool for fluorescence-
significantly improved signal-to-noise ratio (SNR) and an guided surgery, with broad potential in various NIR imaging
approximate penetration depth of 1–3 mm. Particularly, when applications, including photoacoustic imaging.
the emission wavelength falls within the NIR-IIb channel, Li et al. incorporated a pyridine group at the 9-position of
autofluorescence becomes negligible. The exceptional charac- xanthene to develop pyridine-Si-xanthene (Py-SiRh), a near-
teristics of NIR-IIb materials, such as their brightness and high infrared fluorescent platform exhibiting good solubility and
SNR, effectively synergize with 3D confocal imaging techniques, intrinsic targeting ability for lysosomes.180 Py-SiRh showed a
enabling the acquisition of intricate and detailed information red-shifted emission wavelength and good modifiability com-
from biological samples.159,160 pared to traditional Si-rhodamines, making it an excellent
3.1.1. Cancer imaging. After the synthesis of fluorescein58 platform for studying lysosomal cell death. Additionally, a
and rhodamine B,161 xanthene dyes have been widely used for phosphorus-amino-rhodamine (Q-P-ARh) system was prepared,
biofluorescence imaging due to their high fluorescence quan- demonstrating exceptional penetration ability within one min-
tum yield, molar extinction coefficient, excellent photostability, ute and photostability, enabling the monitoring of lipophagy
and easily modifiable modified backbone. In recent years, and capturing its dynamic process, thus greatly facilitating the
researchers have modified rhodamine molecules by increasing study of autophagy pathways (Fig. 13a).166 In 2023, we devel-
the p-conjugation system of the parent nucleus,128 modifying oped Si-NH2-Glu, a novel meso-amine Si-Rhodamine that incor-
the amino substituents at positions 3 and 6,162 amino mod- porates g-glutamyl transpeptidase and pH dual-responsive
ification at position 9,163–166 substitution of heteroatoms at sites, making it suitable for orthotopic tumor imaging and
position 10,167–170 asymmetric modification,171,172 and other fluorescence-guided surgery.86 Additionally, we introduced a

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Fig. 11 (a) Structures of FolateSiR-1 and FolateSiR-2 and their photophysical properties. (b) Fluorescence images of KB cells and OVCAR-3 cells
incubated with FolateSiR-1 or FolateSiR-2 in the presence or absence of folic acid and 0.5% DMSO as a cosolvent. Reproduced with permission from ref.
176 Copyright 2020, Wiley.

combination modification method for optimizing sulfone– higher signal-to-noise ratio for fluorescence imaging. In addi-
xanthone performance by incorporating an amino group at tion, SiR-CTS-pH has a strong differentiation ability for tumour
the meso-position and extending the p-system. This resulted cells and tissues and could accurately distinguish complex liver
in meso-amino-substituted sulfone–xanthone derivatives (J-S- cancer tissues from normal tissues, which shows its great
LS301),181 which exhibited strong fluorescent signals in sub- potential for clinical application.182
cutaneous and orthotopic transplantation tumor models of Fluorescence bioimaging in the near-infrared II (NIR-II)
hepatocellular carcinoma. In 2024, we designed multicoloured window enables the visualization of deep tissue with ultrahigh
and pKa-tunable probes by inserting different heteroatoms on resolution. Simultaneously, there is an urgent need for effective
rhodamine X-10. Moreover, theoretical calculations verified the biosensing in deep tissue, requiring fluorescent probes that can
rationality and developability of the design strategy. Overall, a selectively respond to specific stimuli. NIR-II fluorescent probes
novel and versatile strategy was provided to construct a series of facilitate the visualization of biological and pathological pro-
pyridinamine-functionalized rhodamine probes. Among them, cesses at greater depths.95 While organic fluorophores offer a
Si-4Py possesses a near-infrared emission wavelength, a suita- wide variety of classes with tunable spectral properties, only a
ble pKa, and pH hypersensitivity. Moreover, Si-4Py was applied limited number can absorb and emit in the NIR-II range,
for high-contrast imaging and fluorescence-guided surgery of despite many being available for the NIR-I region (700–
different tumours. It can distinguish peritoneally disseminated 1000 nm). These NIR-II organic fluorophores have demon-
ovarian tumours from normal tissue within 10 minutes, with a strated the highest resolution in vivo fluorescence imaging to
high SNR 4 4.0, and highly accurate tumour identification, date. Traditionally, xanthene-type fluorophores, such as fluor-
together with its broad cancer specificity, making Si-4Py a escein and rhodamine, are primarily regarded as visible-region
particularly effective tool for fluorescence-guided tumour resec- fluorophores. However, Yang et al. recently reported a novel bis-
tion (Fig. 13b).93 In the same year, our group investigated the benzannulated xanthenoid dye (ECX) with a carbon-based
currently available xanthene dyes through a machine learning- bridging group (xanthene) that holds promise for deep-NIR
assisted strategy and constructed a quantitative prediction applications.100 They hypothesize that a silicon analogue of
model to facilitate the rational synthesis of novel fluorescent ECX could enhance these properties. By incorporating an atom
molecules with desired pH responsiveness. Next, we success- of larger radius than carbon, they suggested that increased ring
fully synthesised two novel Si-rhodamine derivatives, and a strain may suppress the vibrational mode.128 Building on prior
series of experiments demonstrated that SiR-CTS-pH has a work, the researchers reported the rational design, synthesis,

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Fig. 12 (a) Chemical structure of DHQ-Rd-PN and its two-photon in vivo fluorescence imaging of ONOO in mice tumor. Reproduced with permission from
ref. 178 Copyright 2020, American Chemical Society. (b) Synthesis pathway of NYL2-NQO1 and the structure of other probes and their photophysical properties
and retention in mice tumors as well as their ability to distinguish tumor boundaries. Reproduced with permission from ref. 179 Copyright 2023, Wiley.

Fig. 13 (a) Structures of P-P-ARh, I-P-ARh, and Q-P-ARh and dynamic movement images of the lipophagy process of 3T3-L1 preadipocytes.
Reproduced with permission from ref. 166 Copyright 2022, Wiley. (b) Multi-color and pKa-tunable platform and the fluorescence images of different
living cells. Reproduced with permission from ref. 93 Copyright 2024, Wiley.

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Fig. 14 (a) Synthesis of EC7 and a PEG-tagged analogue (EC7-PEG5000) and in vivo three-color fluorescence imaging. Reproduced with permission
from ref. 129 Copyright 2023, American Chemical Society. (b) Synthetic route of (S, C(CH3)2)-2XR and the fluorescence images in vivo and in vitro.
Reproduced with permission from ref. 52 Copyright 2024, American Chemical Society.

spectral analysis, and functionalization of the first tetra- fluorophores with remarkably low-energy emission maxima at
benzannulated xanthene dye in its class, demonstrating its 1210 nm. These compounds were constructed by adding para-
potential for biomedical applications through proof-of- substituted styryl groups to the 3 0 ,6 0 -positions of the xanthene
concept two-channel and three-channel models (Fig. 14a).129 core, thereby enlarging the p-conjugation and enhancing the
The imaging of the entire mouse body revealed the temporal electron-donating ability, which effectively increased the dye’s
and spatial variations in fluorescence intensity, reflecting the emission wavelength. Among these, VIX-4 exhibited NIR-II
circulation and distribution of ESi5a in vivo. Using a stereo- fluorescence at 1210 nm with a large Stokes shift and high
microscopic imaging system, finer structures, including micro brightness, enabling the monitoring of blood circulation in the
cerebral blood vessels as small as 30 mm in diameter, were entire mouse body through high-speed dynamic imaging at frame
visualized. Recognizing the significance of bridged atoms in rates up to 200 fps. Blood flow volumes in femoral vessels were
rhodamines, Zhang et al.52 proposed a dual-bridge strategy to directly measured using high spatiotemporal imaging.138 Follow-
create a new scaffold, termed 2X-rhodamine (2XR). This ing this, J. H. Delcamp et al.137 designed and synthesized a series
involved extending the chromophore core with a vinylene of SiRos fluorophores, characterizing their photophysical proper-
moiety to redshift the wavelength and incorporating two atomic ties. SiRos1300, SiRos1550, and SiRos1700 displayed emission
bridges, X1 and X2, which formed five- and six-membered rings maxima at 1300 nm, 1557 nm, and 1700 nm, with fluorescence
to enhance the structural rigidity and reduce nonradiative quantum yields of 0.0056%, 0.0025%, and 0.0011%, respectively.
decay. Consequently, the 2XR scaffold, featuring sulfur (S) at In vivo NIR-II imaging experiments were conducted using
X1 and C(CH3)2 at X2, exhibited absorption and emission peaks SiRos1300 and SiRos1550 in canola oil-based nanoemulsions,
at approximately 715 nm and 765 nm, respectively, along with a achieving full circulatory distribution and high-resolution ima-
bright emissive tail beyond 1000 nm, high quantum yield (FF = ging of mouse vasculature in the femoral arteries, abdominal
0.11), long fluorescence lifetime (t = 1.1 ns), and notable cavity, and jugular veins. In 2019, Lei Z et al.183 developed a series
log KL–Z value of 1.8 under aqueous conditions (Fig. 14b). of wavelength-tunable, highly stable NIR-II fluorescent dyes (CX-1,
Expanding the conjugated structure is an effective approach to CX-2, and CX-3), which demonstrated superior chemical and
redshift the absorption and emission wavelengths of photostability in aqueous solutions and outperformed ICG in
fluorescent probes. One direct method is replacing the 30 ,6 0 - in vivo lymphatic imaging applications.
hydroxyls with sp2 carbon. A recent advancement involved synthe- ‘‘Always-on’’ NIR-II fluorophores for bioimaging often pro-
sizing an NIR-II-emitting xanthene-based fluorophore by substi- duce unwanted background signals due to accumulation in
tuting indolizine heterocycles for alkyl amine donors, resulting in non-target areas. In contrast, activatable NIR-II probes can alter
a B400 nm (1.01 eV) bathochromic shift in the absorbance to their fluorescence emission wavelength or intensity in response
930 nm and an SWIR emission maximum at 1092 nm.131 In 2021, to specific physiological parameters or clinically relevant ana-
Ma et al. para-functionalized styrene-based donors, yielding lytes, resulting in higher SNR, greater specificity, and lower

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Fig. 15 (a) Structures of PN910 and in vivo monitoring of cystitis with PN910. Reproduced with permission from ref. 187 Copyright 2021, Wiley. (b) NIR-II
fluorescence imaging of LPS-induced lymphatic inflammation using the NIRII-HD5-ONOO probe. Reproduced with permission from ref. 188 Copyright
2022, Wiley. (c) In vivo detection of endogenous ATP in the livers of mouse during APAP-induced hepatotoxicity by the NIRII-RT-ATP probe. Reproduced
with permission from ref. 51 Copyright 2020, Wiley. (d) Structure of CX-RATP and proposed mechanism for ATP detection and NIR-II imaging in vivo.
Reproduced with permission from ref. 189 Copyright 2023, Wiley.

detection limits compared to traditional ‘‘always-on’’ detecting these species without false positives. This work
fluorophores.184–186 NIR-II xanthene fluorophores have been provides a simple yet effective tool for monitoring H2O2 and
tailored to create off–on probes for biosensing, capitalizing on ONOO associated with various diseases in alkaline environ-
their flexible modification capabilities and tunable wave- ments. To further enhance the versatility of NIR-II activatable
lengths. For instance, the groups of Zhang and Lei developed small-molecule probes, Yuan’s group designed a platform
an NIR-II fluorescent probe, PN910, that selectively targets based on the intramolecular charge transfer (ICT) mechanism,
H2O2 and ONOO at pH levels above 7.4, demonstrating high creating probes for analytes such as reactive oxygen species
selectivity and deep tissue penetration in vivo (Fig. 15a).187 In (ROS), thiols, and enzymes (Fig. 15b).188 This development not
mouse models of cystitis and colitis, PN910 exhibited a sig- only resulted in multiple NIR-II activatable probes for different
nificant enhancement in fluorescence compared to control diseases in mouse models but also established a paradigm for
groups, and biochemical analysis confirmed its reliability in broader analyte testing within NIR-II biosensing. Similarly, in

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2021, Yuan et al.51 introduced the ATP-activatable NIR-II probe images of blood vessels over the body, but it requires the use of
NIR-RT4 for imaging drug-induced hepatotoxicity in vivo contrast agents, which may cause problems such as allergies or
(Fig. 15c). NIR-RT4, containing a rhodamine spirolactone, kidney damage. MRA has the advantage of no radiation and the
exhibited no fluorescence due to the disruption of its p- ability to provide soft tissue contrast. However, they have a
conjugate system. Upon reacting with ATP, the spirolactone higher cost and greater equipment requirements. Contrast
ring opened, restoring the p-conjugate system and resulted in a agents may cause discomfort and are not usable in some cases
fluorescence emission increase at 918 nm. The selectivity of (e.g., in people with renal insufficiency). In recent years, emer-
NIR-RT4 for ATP was validated by comparing its responses to ging vascular imaging techniques including optical imaging
other biological species, including ADP, AMP, GTP, and (e.g., near-infrared imaging) and fluorescence imaging have
biothiols. Given ATP’s role as a critical signaling molecule in occurred. Due to their advantages of non-invasiveness, real-
damaged and stressed cells, NIR-RT4 was utilized to monitor time imaging, and high contrast, they can not only observe
drug-induced hepatotoxicity through ATP fluorescence. Signifi- micro vessels but also monitor intraoperative bleeding in real
cant increases in NIR-II fluorescence were observed in aceta- time and be used for surgical navigation. Xanthine-based
minophen (APAP)-induced hepatotoxicity, with fluorescence fluorescent dyes have great potential for vascular imaging
intensifying with longer APAP treatment durations. Addition- applications due to their high sensitivity, high selectivity, good
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ally, hepatotoxicity induced by CCl4 was also monitored via biocompatibility, real-time imaging capability and low back-
in vivo NIR-II imaging. In 2023, Zhang’s group189 established a ground interference. In 2019, Shi et al. synthesized a series of
reversible NIR-II FRET-based molecular fluorescent probe, CX- rhodamine-benz[c,d]indolium analogues (Rh824, Rh926, and
RATP, for in vivo ATP detection (Fig. 15d). CX-RATP demon- Rh1029) using a polyene bridging strategy. They demonstrated
strated selective and reversible responses to ATP, along with that the photophysical properties of these fluorophores could
excellent biocompatibility. This probe allows for the real-time be modulated by varying the number of vinylene moieties. To
recording of fluctuations in ATP levels in response to various further enhance the quantum yield of Rh1029, the dye was self-
drugs, making it a valuable tool for monitoring dynamic assembled with phosphatidylcholine (PC), which improved its
physiological changes. Furthermore, as an NIR-II ratiometric water solubility and increased the fluorescence quantum yield
probe, CX-RATP possesses the advantages of quantitative detec- threefold. Notably, they applied Rh1029-PC for the first time as
tion of ATP in deep tissues and has been successfully applied an angiographic agent in the NIR-II window. The high spatial
for in situ imaging. Given its outstanding spectral properties resolution of NIR-II imaging enabled Rh1029-PC to effectively
and high performance in vivo, CX-RATP holds promise for label hemorrhage locations in a mouse vascular hemorrhage
various clinical biomedical applications and may inspire the model (Fig. 16a).190 In a separate study, Ma et al. developed a
development of additional NIR-II ratiometric fluorescent new series of rhodamine derivatives termed VIXs, which exhibit
probes. red-shifted fluorescence in the NIR-II window by extending
3.1.2. Blood vessels imaging. Blood vessels are spread all p-conjugation and enhancing intramolecular charge transfer
over the human body. Vascular imaging is an important (ICT) effects. They achieved this by coupling two styryl groups
technique in medical imaging and is mainly used to visualise to the 3 0 and 6 0 positions of rhodamine, while incorporating the
the structure of blood vessels and blood flow. Vascular imaging electronically competent julolidinestyryl to create high-
plays a crucial role in medicine. It not only helps to detect and performing VIX-4, which emits fluorescence at 1210 nm, a
treat diseases but also improves medical safety and therapeutic significant achievement, as it is rare for organic fluorophores
efficacy. In terms of diagnosing diseases, vascular imaging to exceed 1200 nm. The effectiveness of this design strategy was
could help doctors to diagnose various vascular-related dis- further supported by molecular theory calculations. VIX-4 was
eases such as atherosclerosis, thrombosis, aneurysms and utilized for high-speed dynamic imaging of the whole-body
vascular malformations. In terms of guiding treatment, vascu- circulatory system of mice at frame rates up to 200 frames
lar imaging provides doctors with real-time images of blood per second, allowing for the direct measurement of blood flow
vessels during interventional procedures, allowing them to volumes in the femoral vessels using high spatiotemporal
perform interventions such as stent placement and vasodilata- imaging. This study not only provided an important tool for
tion more accurately. Moreover, before performing major sur- high-resolution bioimaging but also established a valuable
gery, vascular imaging could help assess the patient’s vascular framework for future NIR-II fluorescent probes (Fig. 16b).138
status, thus providing an important basis for surgical planning 3.1.3. Neuroimaging. The nervous system is the dominant
and reducing surgical risks. Traditional vascular imaging tech- system in the human body that responds to physiological
niques include X-ray angiography, computed tomography activities and external stimuli. Neuroimaging plays an impor-
angiography (CTA), and magnetic resonance angiography tant role in diagnosing neurological diseases and in analysing
(MRA). They have advantages and disadvantages. X-ray angio- brain microstructure and cognitive functions. During surgery,
graphy could provide high-resolution vascular images and is if the nerve is accidentally transacted or damaged, it would lead
suitable for the diagnosis of most vascular lesions. However, it to partial functional decline or even permanent loss. Presently,
is more invasive, requires the insertion of a catheter, and poses conventional neuroimaging modalities, such as magnetic reso-
a risk to people who are allergic to contrast media. CTA has the nance imaging (MRI), computed tomography (CT), and high-
advantage of non-invasiveness and the ability to quickly obtain resolution ultrasound (US), could provide image guidance to

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Fig. 16 (a) Images of hindlimbs of nude mice intravenously injected with Rh824-PC. Reproduced with permission from ref. 190 Copyright 2019,
American Chemical Society. (b) NIR-II fluorescence images of BALB/c mice with VIX3 (row 1 and 2) and VIX-4 (row 3 and 4) liposomes. Reproduced with
permission from ref. 138 Copyright 2021, American Chemical Society.

the surgeon during the surgical procedure. However, the opera- development of fluorescence-guided surgery, the use of fluor-
tion of the system conforms to the normal surgical procedure escent substances to mark the target area allows for intraopera-
and prolongs the operation or anaesthesia time. At the same tive real-time colour contrast. This technique improves surgical
time, the drawbacks of its expensive price and huge footprint precision by illuminating the target tissue, which has been
affect intraoperative use. Due to the similar signal intensity labelled with a fluorescent dye, with different wavelengths of
between peripheral nerves and peripheral tissues, in practice, light. This technology could achieve pico-level sensitivity and
MRI could only identify the brain and spinal cord but not micron-level spatial resolution, with hundreds of images
peripheral nerve tissues. High-resolution ultrasound is one of per second and more intuitive fluorescence images. Among
the methods used for peripheral nerve examination, but it is them, near-infrared fluorescence imaging could penetrate more
only effective for superficial nerves because it is based on a deeply and effectively into biological tissues such as skin and
network of hypoechoic bands and hyperechoic lines. In surgery, blood in the application of optical imaging because the wave-
surgeons differentiate between target tissues largely by looking length is not easy to be absorbed and scattered by biological
at the colour, texture and morphology of the tissues, and these tissues, which makes it stand out in fluorescence-guided surgi-
features provide critical information to help the surgeon deter- cal operations and gradually forms a new technology, new
mine the correct treatment approach and manipulation tech- equipment, and new clinical discipline of near-infrared fluores-
nique. Since the anatomy of nerves varies greatly from patient cence imaging-guided surgical operations. Xanthene-based
to patient and nerves are often hidden underneath the protec- functional dyes as near-infrared II region visualiser (NIR-II)
tive layer of tissues, the above techniques are not able to could achieve lower tissue autofluorescence, photon scattering
accurately locate the nerves and develop the anatomical details and absorption, with higher SBR and deeper penetration into
required for treatment planning, and some of them have biological tissues and have promising applications in neuroi-
potential radiological risks. Therefore, intraoperative identifi- maging. PARK et al. successfully established a library of highly
cation of the relevant nerves mainly relies on the surgeon’s neural-specific fluorescent motifs by synthetically modifying
knowledge of anatomical location, skilful surgical techniques, oxazine fluorophores with near-infrared spectra using oxazine 1
and extensive clinical experience. In recent years, with the and oxazine 4 as scaffolds.191 Wang et al., screened four oxazine

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Fig. 17 (a) Nerve specificity of the potential lead NIR oxazine derivatives. Reproduced with permission from ref. 192 Copyright 2020, American
Association for the Advancement of Science.

derivatives (LGW01-08, LGW05-75, LGW04-31 and LGW03-76) neural tissue targeting and rapid off-target tissue clearance by
by in vivo neurofluorescence testing. Compared with other comparing the fluorescence intensity of oxazine 4 with rhoda-
moieties, among them, oxazine 4 showed better experimental mine red in neural tissue.194
results in terms of neural specificity as well as development
time and successfully identified and highlighted the laryngeal 3.2. Cancer therapy
recurrent nerve of pigs in real time, while oxazine 1 did not Xanthene dyes are well known for their high singlet oxygen
show neural specificity, although it had a high structural quantum yield and utility as triplet photosensitizers (PSs) in
similarity with oxazine 4 (Fig. 17).192 In 2017, there was a study PTT/PDT. They are mainly planar aromatic compounds with a
that took advantage of the different spectral properties of dibenzofuran (xanthene) structure, and a large number of
oxazine 4 and Nile red to achieve fluorescence of nerve and photosensitisers have been developed for cancer therapy by
adipose tissue separation by a dual-colour imaging strategy in a substituting oxygen atoms and modifying rhodamine with
locally administered manner.193 In 2019, a study continued to other elements, such as Si, S, P, Ge, Sn, and Te. In 2004, Detty
explore the effects of partition coefficient and overall charge on et al. developed a series of rhodamine derivatives with sulfur

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Fig. 18 (a) Structures of TMR-O, TMR-S, TMR-Se and their photophysical properties. (b) Structures of 15a-18b and their photophysical properties. (c)
Structures of 6-s–7-Se and their photophysical properties. (d) Synthetic routes of PY-P and P2. Reproduced with permission from ref. 201 Copyright
2020, The Royal Society of Chemistry. (e) FRET-based SIT phototheranostic (RDM-BDP) for amplified 1O2 generation, native tumor targeting as well as
light-triggered enhanced tumor PDT. Reproduced with permission from ref. 202 Copyright 2018, American Chemical Society. (f) Structure of Rh-NBSe
and its application in PDT. Reproduced with permission from ref. 203 Copyright 2021, The Royal Society of Chemistry.

and selenium atoms, replacing the oxygen atom in the parent 9.0  108 M and 1.8  107 M, respectively (Fig. 18c). In March
nucleus of the xanthene to improve the 1O2 yield (TMR-O, TMR- 2022, Kida et al. proposed a design strategy to transform
S, TMR-Se, Fig. 18a).195 Moreover, a (2-thienyl) substituent was fluorescein into a type I photosensitiser by inducing charge
introduced at position 9 to facilitate the transport of the separation (CS) through the self-assembly of fluorescein.198 The
molecule through the absorption of P-glycoprotein and CS state of fluorescein may have an energy level lower than the
expanded the conjugation system to regulate the maximum T1 energy level, and the CS state could be generated by
absorption wavelength of the molecule to 4600 nm, which is symmetry-breaking charge separation (SB-CS) and charge car-
an ideal wavelength for the photosensitiser. Selenorhodamine rier migration in self-assembly.199 It was shown that the CS
photosensitizers are used for the photodynamic therapy of state energy levels of fluorescein self-assembled supramole-
P-glycoprotein-expressing cancer cells (Fig. 18b).196 Two years cules were lower than those of the triplet states, i.e., FI-C18
later, their group197 further extended the wavelength of the formed the S1 state upon illumination and was converted to the
previously available selenium-substituted, sulfur-substituted CS state either directly or via the SB-CS triplet state. On
rhodamine molecules to 4640 nm. The half-effect concentra- the contrary, FI-C2 loses the absorbed energy mainly
tions (EC50) of 7-S and 7-Se obtained for Colo-26 cells were through fluorescence and enters the triplet state through ISC.

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In October of the same year, based on the previous studies, the different luminescent transition metal systems (M-Rho) with
group fabricated a type I supramolecular photosensitiser self- rhodamine, significantly enhancing the generation of the tri-
assembled from a simple amphiphilic rhodamine Rh9-MA-C18. plet excited state and 1O2 formation under visible light208.
Rh9-MA-C18 NPs had a high O2 yield and were effective for Wong et al. further optimized cyclometallic ligands to develop
PDT in human lung cancer cells PC9 node mice.200 In 2022, the novel rhodamine-based PS Ir-Rho-G2, which demonstrated
Zhou et al.201 proposed to introduce phosphate as a strong increased capacity for singlet oxygen generation and targeting
electron-absorbing group at the meso-position of the xanthene of the endoplasmic reticulum.205
to form a push–pull electron structure with the electron- Hypoxia is a common feature of most tumors. Piao et al.
donating ability of the parent nucleus of the xanthene, which constructed a selenium-rhodamine photosensitizer (azoSeR)
is conducive to electron transfer. Experiments showed that PY-P capable of producing 1O2 even under hypoxic conditions
was a pure type I photosensitizer, and after encapsulation with (Fig. 19).206 Additionally, the overexpression of specific
Pluronic F127 to form nanoparticles, it had strong cytophoto- enzymes, such as g-GGT, serves as a hallmark of the tumor
toxicity for Hale cells in both normoxia and hypoxia (Fig. 18d). microenvironment. In 2017, Urano et al.207 introduced the
The introduction of a strong electron-absorbing group made photosensitizer gGlu-HMSeR specifically responsive to g-GGT,
the molecule red-shifted for absorption and also had good which can generate 1O2 for tumor therapy. In 2019, Zhang
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fluorescence emission (FF = 0.35), which had great potential et al.208 developed a p-extended red-absorbing activatable Se-
for fluorescence-directed PDT in solid tumours at 626 nm. In rhodamine (Se-NR-Az) photosensitizer, extending its maximum
2018, Li et al. developed a novel rhodamine derivative, PS RDM- absorption wavelength to 616 nm, optimizing it for the ther-
BDP, utilizing Förster Resonance Energy Transfer (FRET) and apeutic window (600–900 nm) and enhancing its biological
SIT.202 At 557 nm, RDM-BDP exhibited a strong absorption applications. That same year, Peng et al. reported the FUCL
peak, and under near-infrared (NIR) irradiation, it generated a strategy, employing a one-photon molecular upconversion rho-
linear state of singlet oxygen (1O2) effective for cancer cell damine derivative (FUCP-1). In contrast to conventional Stokes
apoptosis (Fig. 18e). Similarly, Peng et al. employed this strat- emission, FUCP-1 can be excited at longer wavelengths
egy to create a FRET-based photosensitizer, Rh-NBSe, by con- (808 nm), achieving a remarkable upconversion quantum yield
jugating rhodamine with benzo[a]phenoselenazinium. Under (412%) along with excellent optical stability. In vivo studies
light, Rh-NBSe produced 1O2 and cleaved in the presence of indicated that FUCP-1 was selectively concentrated at tumor
reactive oxygen species, releasing rhodamine fluorophores and sites, resulting in a 73.7% tumor growth inhibition rate after
thus restoring the fluorescence inhibited by FRET. This fluores- PDT.209 To further enhance deep tumor photodynamic therapy
cence signal conversion mechanism can effectively reflect the (dPDT), Ma et al. introduced a ‘‘booster effect’’ strategy that
real-time production of singlet oxygen in photodynamic ther- constructs effective phototherapeutics through hot band
apy (PDT) (Fig. 18f).203 However, rhodamine alone does not absorption. They systematically investigated various rhodamine
produce 1O2 upon light exposure, prompting researchers to derivatives containing different heteroatomic aromatic rings,
devise various strategies for its conversion into photosensiti- such as FUC-N (no heavy atom), FUC-S (internally weak heavy
zers. Liu et al.204 proposed a versatile approach by complexing atom S), FUCP-1 (peripheral strong heavy atom I), and FUC-Se
(internally strong heavy atom Se).210 This selenium-based strat-
egy significantly improved the photosensitization performance
of anti-Stokes photosensitizers and advanced their clinical
application. In 2024, our team synthesized three new photo-
sensitizers (SN-1, SN-2, and SN-3) by introducing phenyl and
electron-rich five-membered heterocycles at the meso position
of S-rhodamine. In these compounds, the phenyl (SN-1), furyl
(SN-2), and thienyl (SN-3) groups acted as electron donors,
while the rhodamine backbone served as an electron acceptor.
Reactive oxygen species (ROS) tests revealed that SN-1 func-
tioned as a hybrid type I and II photosensitizer, while SN-2 and
SN-3 were pure type I photosensitizers. Further in vivo studies
demonstrated that SN-3 effectively inhibited solid tumors in
hypoxic conditions.57 In another innovative approach, we con-
structed novel type I photosensitizers by lowering the triplet
state (T1) energy level and enhancing donor–acceptor (D–A)
interactions. We selected dibenzofurstene (FE) as the backbone
for its high conjugation and ability to reduce the T1 level.
Amino groups were introduced as donors, while electrophilic
Fig. 19 Structure of azoSeR and inhibited solid tumors under hypoxia.
groups served as acceptors, resulting in a series of
Reproduced with permission from ref. 206 Copyright 2021, The Royal dibenzofurstene-based type I photosensitizers (FE-VSM, FE-
Society of Chemistry. MDN, FE-TCF, and FE-TMI). Among them, FE-TMI exhibited

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Fig. 20 (a) Schematic of BH 1024 NPs’ preparation, application and the NIR-II fluorescence imaging-guided PTT. Reproduced with permission from ref.
211 Copyright 2021, Wiley. (b) NIR-II fluorescence images of 4T1 tumor-bearing mice at different time points after injecting BHcy-NPs. Reproduced with
permission from ref. 212 Copyright 2022, Wiley. (c) Schematic of CN3 NPs’ preparation and application. Reproduced with permission from ref. 213
Copyright 2023, Elsevier.

the most promising PDT efficacy, validated in a triple-negative conjugation system, minimizing internal deactivation and stabi-
breast cancer (TNBC) mouse model, demonstrating significant lizing the excited state, thus achieving a balance between NIR-II
anti-tumor effects.77 fluorescence, oxygen photosensitization, and photothermal per-
Over the past decade, organic photothermal therapy (PTT) formance. BH1024, in particular, exhibited outstanding perfor-
agents have emerged as promising alternatives or complements mance with high photothermal conversion efficiency and singlet
to traditional therapies. Xiao et al. introduced a rigid xantho- oxygen generation under 1064 nm laser irradiation (FF = 0.5%,
nium moiety in cyanine dyes, resulting in novel near-infrared FD = 0.07, ZPCE = 41.3%). This deep tissue penetration enabled
(NIR)-II xanthonium-cyanine dyes (BHs, Fig. 20a).211 This mod- effective tumor treatment via both NIR-II PDT and PTT in mouse
ification produced a significant 400 nm redshift in maximum models, marking the first identification of a small-molecule dye
absorption compared to traditional iodolium-based cyanine capable of directly generating singlet oxygen upon NIR-II laser
dyes. The xanthonium core enhanced the rigidity of the excitation, providing insights for future photosensitizer designs.

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Building on this, Xiong et al. employed an acceptor engineer- successfully conducted NIR-II/photoacoustic imaging-guided
ing strategy to create a near-infrared, heavy-atom-free tumor ablation and PDT/PTT therapy under NIR laser irradiation.
hemicyanine-based photosensitizer (BHcy) for NIR-II fluore- Although xanthene-based NIR organic phototheranostics
scence-guided PTT and PDT (Fig. 20b).212 A planar, rigid agents-mediated PDT/PTT have made great progress in tumor
p-conjugated moiety (1-ethyl-benz(c, d)iodolium) was utilized as therapy, however, they still have many shortcomings and
the acceptor. BHcy displayed redshifted absorption and emission challenges similar to other photosensitizers. Firstly, the largest
at 770 and 915 nm, respectively, compared to Hcy. Theoretical problem is the limited depth of light penetration, which may
calculations indicated enhanced planarity and rigidity of BHcy’s result in the incomplete ablation of tumors. Secondly, the
conjugated system, which reduced the HOMO/LUMO energy gap conversion efficiency of some photothermal transduction
and improved singlet oxygen generation through enhanced spin– agents (PTAs) is low, and some strategies are required to
orbit coupling and intersystem crossing (ISC). This increased improve the efficiency of photothermal transduction to better
rigidity facilitated intermolecular p–p interactions, enhancing treat tumors. In addition, the therapeutic effect of solely PDT/
vibrational coupling and photothermal conversion. Nanoparticles PTT is limited, and taking PDT/PTT combined with chemother-
formed by combining BHcy with DSPE-PEG2000 demonstrated apy, radiotherapy, targeted therapy and immunotherapy could
excellent photothermal conversion and photosensitizing capabil- improve the therapeutic effect. Furthermore, the biosafety of
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ities (FD = 0.129, ZPCE = 55.1%), showcasing significant anti-tumor photosensitizers is particularly important. The current mouse
properties both in vitro and in vivo. tumor models commonly used in preclinical experiments are
Wang et al. introduced a structural bacterial targeting strat- insufficient to reflect the physiological conditions of clinical
egy using NIR-II xanthene dyes (CNs) for effective photothermal patients. In order to promote the clinical application of PDT/
antibacterial therapy (Fig. 20c).213 The extended p-conjugated PTT, it is necessary to evaluate the therapeutic efficacy and
structure of CNs resulted in intense absorption bands at about safety in other large animals such as dogs, pigs and monkeys.
1180 nm. To improve water solubility and biocompatibility, In conclusion, the development of new strategies or the optimal
CNs were encapsulated in Pluronic F127 to form liposomes (CN combination of existing strategies will surely contribute signifi-
NPs) via membrane hydration. Due to H-aggregate formation cantly to the application of xanthene-based NIR organic photo-
from p–p stacking, CN NPs exhibited blue-shifted absorption theranostics agents in cancer PTT/PDT, which provides an
peaks and high NIR-II photothermal conversion efficiencies attractive and challenging opportunity to further enhance the
(approximately 40%). CN3 NPs showed a more positive zeta effectiveness of anticancer therapy.
potential than related liposomes, as intermolecular hydrogen
bonding within the CN3 dimer embeds the carboxyl group, 4. Conclusion
exposing the positively charged xanthene skeleton. This
configuration endowed CN3 NPs with inherent bacterial target- This study focuses on reviewing the recent developments in
ing capability, significantly enhancing their photothermal bac- xanthene dyes and their structural modifications, exploring the
tericidal activity against both Gram-positive and Gram-negative imaging and sensing technologies based on these fluoro-
bacteria in vitro and in vivo (99.4% and 99.2% effectiveness phores, as well as summarizing the potential applications of
against S. aureus and E. coli, respectively). Furthermore, the these dyes in diagnosis and therapy. In recent years, the rapid
NIR-II photothermal effect of CN3 NPs effectively inhibited advancement of NIR-II phototherapeutic technologies has dri-
infection and promoted wound healing without systemic toxi- ven the development of high-performance xanthene-based
city, highlighting the potential of this targeting strategy for phototherapeutic agents. Consequently, researchers have
clinical antimicrobial therapy. proposed various modification methods to enhance these dyes.
Our team is also investigating xanthene derivatives for These modification strategies have been thoroughly validated
tumor PDT/PTT. In 2023, we selected 3,6-diethylamino- as effective and versatile means to significantly improve
fluorenone (FE) as the core for two donor–p–acceptor (D–p–A) xanthene dyes exhibiting NIR-I/II emission and large Stokes
photosensitizers (PTAs), FE-BA and FE-IDMN by replacing the shifts. Such strategies enrich the toolkit of researchers in
carbonyl group with electron-withdrawing groups (EWGs).76 chemistry, biology, and medical science, facilitating the devel-
Notably, FE-IDMN in nanoparticle form (FE-IDMN NPs) exhib- opment of high-quality NIR-I/II fluorophores for a wide range of
ited a high photothermal conversion efficiency (PCE) of 82.6%. applications, ranging from detecting bioactive and environ-
These nanoparticles demonstrated excellent colloidal, pH, and mental species to imaging-guided cancer therapy.
photothermal stability, enabling multimodal imaging (NIR-II However, due to inherent limitations in the xanthene struc-
FLI, PAI, and PTA)-guided PTT of subcutaneous tumors in mice, ture, many of these modification strategies struggle to further
successfully ablating the 4T1 tumor under NIR laser irradiation. extend the emission wavelengths of compounds into the NIR II
In the same year, we designed and synthesized a series of PTAs region. There are still many under-explored areas regarding the
named as ICRs, utilizing rigid Si-xanthene as donors and posi- modification and biological applications of xanthene.
tively charged benz[e]indole as acceptors.20 Among these, the ICR-
Qu nanoparticle formulation exhibited the highest physiological 4.1. Enhancing emission efficiency
stability, biocompatibility, a high PCE (81.1%), and effective Strategies to reduce the p–p stacking of these fluorophores and
ROS generation, achieving superior anti-tumor efficacy. We to hinder interactions between water molecules and the

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fluorophores through bulky alkyl substituents may improve the Acknowledgements

emission efficiency. Moreover, extending the p-conjugated sys-
tem and introducing cationic p systems are effective methods This work was financially supported by the National Natural
to enhance the absorption efficiency. Science Foundation of China (U21A20308, 22077088), the
Science and Technology Major Project of Tibetan Autonomous
4.2. Absorption wavelength limitations Region of China (XZ202201ZD0001G) and the Science and
Technology Innovation Seedling Project of Sichuan Province
The absorption capabilities of xanthene dyes often fail to (Grant No:2024JDRC0041).
effectively transfer to the near-infrared absorption range. For
instance, the emission wavelengths of classic xanthene repre-
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