Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications

Journal of Rare Earths xxx (xxxx) xxx

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Journal of Rare Earths journal homepage: http://www.journals.elsevier.com/journal-of-rare-earths

Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications* Suwan Ding, Lingfei Lu, Yong Fan**, Fan Zhang* Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers and iChem, Fudan University, Shanghai 200433, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 November 2019 Received in revised form 31 December 2019 Accepted 22 January 2020 Available online xxx

The second near-infrared (NIR-II, 1000e1700 nm) window provides a superior optical platform with high resolution, deep penetration and high signal-to-noise ratios (SNRs), which results from the intrinsic low scattering and autofluorescence in biological tissues. As one of the promising NIR-II emitting probes, lanthanide based nanoparticles (LnNPs) exhibit high photo stability and chemostability, long photoluminescence lifetimes, low long-term cytotoxicity and narrow emission bandwidths. All these merits have spurred the evolution of related bio-optics and a variety of biomedical applications of LnNPs. This mini-review discusses the most recent advances in both the design e the composition and surface modifications e and the applications of NIR-II emitting LnNPs in bioimaging, disease diagnosis and therapy. We also summarize the current limits and challenges facing the applications of LnNPs as well as discuss the directions of future development. © 2020 Published by Elsevier B.V. on behalf of Chinese Society of Rare Earths.

Keywords: Lanthanide nanoparticles Second near infrared window Fluorescence imaging Diagnose Therapy Rare earths

1. Introduction The second near-infrared (NIR-II, 1000e1700 nm) window, extending from the first near-infrared (NIR-I, 700e900 nm) window, is a recently developed region with intrinsically great penetration depths and low background noise in biological tissues and consequently has spurred a series of breakthroughs in biomedical applications. Optics for biotechnology and medicine is constantly accompanied by light-tissue interactions, including reflection, scattering, absorption and autofluorescence1 (Fig. 1(a)). Among the four processes, scattering is regarded as a major source of high background noise and it impairs the penetration depths by diminishing the energy along the way. Compared with the visible and NIR-I regions of shorter wavelengths, the NIR-II optical window

* Foundation item: Project supported by the National Key R & D Program of China (2017YFA0207303), National Science Fund for Distinguished Young Scholars (21725502), Key Basic Research Program of Science and Technology Commission of Shanghai Municipality (17JC1400100) and Intergovernmental International Cooperation Project of Science and Technology Commission of Shanghai Municipality (19490713100). * Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (Y. Fan), [email protected] (F. Zhang).

engages in minimal scattering, since the degree of scattering in tissues decreases with increasing wavelengths in nearly all kinds of biological tissues.2e4 Thus, high signal-to-noise ratios (SNRs) and deeper penetration depths are more likely to be achieved. Meanwhile, autofluorescence that comes from endogenous fluorophores in tissues also decays sharply with increasing wavelengths. The region above 1500 nm is almost autofluorescence-free.5,6 In the NIR-II window, autofluorescence is generally low, which helps raise the SNR as well. Besides, higher maximum permissible exposure (MPE) on biological tissues is possible because of the low photon energy at long wavelengths,1,7 allowing higher applicable laser power density in the NIR-II window than that in the NIR-I region. It should be noted that water absorption bending overtone at around 1450 nm is typically avoided.8 With higher resolution, greater penetration depths (above 1 cm) and higher SNRs,9,10 the technology of NIR-II fluorescence has attracted massive attention in the quest for high-quality bio-optical solutions. So far, the most developed types of NIR-II fluorescence probes include quantum dots,11e14 organic dyes,15e19 conjugated polymers,17 single-walled carbon nanotubes,20e23 and lanthanidebased nanoparticles (LnNPs).24e30 However, quantum dots usually contain toxic elements like lead and cadmium; organic dyes suffer from photo bleaching, small Stokes shifts, as well as easy degradation; conjugated polymers, along with organic dyes, tend

https://doi.org/10.1016/j.jre.2020.01.021 1002-0721/© 2020 Published by Elsevier B.V. on behalf of Chinese Society of Rare Earths.

Please cite this article as: Ding S et al., Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications, Journal of Rare Earths, https://doi.org/10.1016/j.jre.2020.01.021

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to have low solubility in aqueous solutions, forming aggregation; single-walled carbon nanotubes display emission over a broad range on the spectrum (hundreds of nanometers). All these drawbacks limit the quality and compatibility of NIR-II bioimaging. NIR-II emitting LnNPs, on the other hand, possess many advantages, including high photo stability and chemostability, low long-term cytotoxicity and narrow emission bandwidths. Although LnNPs suffer from the low brightness due to the spinforbidden f-f transitions, this trait compensates by long radiative lifetimes of the excited states which can be harnessed to eliminate the tissue autofluorescence (lifetime at nanosecond range) through time-gating technology.31 This mini-review summarizes recent progress where cuttingedge refinements of NIR-II emitting LnNPs are made and the strengths of LnNPs in NIR-II biomedical optics, including bioimaging, disease diagnosis and therapy are demonstrated (Fig. 1(b)). Firstly, there are novel chemical and structural designs of LnNPs, including new host materials, doping ions and concentration, and new formulas of chemical composition. Furthermore, extensive and creative studies on the surface modifications of LnNPs have yielded huge improvement in the optical performance e brighter and more stable fluorescence e as well as the biochemical activity and compatibility. All these processes have played critical roles in the NIR-II emitting LnNPs in many biomedical applications.

Fig. 1. (a) Schematic illustration of light-tissue interaction; (b) Schematic illustration of the design elements and bio-optical applications of NIR-II emitting LnNPs.

2. Novel designs of NIR-II emitting LnNPs 2.1. Constitutions and mechanisms of the NIR-II emitting LnNPs The LnNPs are generally made up of host matrices, sensitizers and activators. The host matrix should be optically transparent. The sensitizers as well as the activators are generally lanthanide ions in the þ3 oxidation state. In the crystal field maintained by the host matrix, the excited states of both the sensitizers and the activators split into different energy levels in a ladder-like manner. Under laser irradiation with proper wavelengths, electrons of the sensitizers are first excited and then transfer the energy to the activators. The subsequently excited activators emit luminescence as the excited electrons return to the ground states. Table 1 summarizes typical compositions of NIR-II emitting LnNPs in recent progress. A core/shell structure is often utilized to enhance the optical performance of NIR-II emitting LnNPs (Fig. 2(a)). The core usually contains both sensitizers and activators, which is the source of NIRII emissions. The shell can be either inert or active. In some cases, multi-layered shells are engineered (Table 1). Inert shells composed of optically inactive materials like NaYF4 or NaLuF4 are used to encapsulate the core. The epitaxial growth of an inert shell is sufficient in passivating surface defects and thus reducing surfacerelated quenching of the core.32 Active shells contain activators and/or sensitizers. Besides reducing surface defects,33 they may undergo energy transfer with other dopants in the core and among different shells, which affords better optical tunability of the LnNPs.25 To generate NIR-II emission, Yb3þ is usually used as the sensitizer for Ln3þ activators (Ln ¼ Ho, Pr, Er or Tm to give emissions at 1155, 1289, 1525 and 1475 nm, respectively) (Fig. 2(b)). After Yb3þ absorbs the 980 nm illumination, energy transfers from Yb3þ to excite the Ln3þ activators. The Yb3þ-Er3þ (sensitizer-activator) pair with Ce3þ and Zn2þ doping has been recently reported to generate bright NIR-II illumination (Fig. 2(c)).34 The cross-relaxation (CR) between Er3þ (4I11/2 / 4I13/2) and Ce3þ (2F5/2 / 2F7/2) depopulates the 4I11/2 state of Er3þ, suppressing the transition to higher states which leads to upconversion, and populates the 4I13/2 state, consequently boosting the 1550 nm emission.35 Meanwhile, it was interestingly proposed that Zn2þ-doping contributed to the improvement of both brightness and lifetime by reducing crystal field symmetry. As for the Yb3þ-Tm3þ pair, Tm3þ is excited through a two-photon upconversion process. Note that the Yb3þ-Tm3þ and Yb3þ-Pr3þ pairs are rather limited in applications due to weak NIRII emissions.28,36 In some cases, Nd3þ and Er3þ can also serve as sensitizers. Nd3þ is employed to sensitize Ln3þ activators such as Er3þ through the efficient energy transfer to Yb3þ, yielding the 1525 nm emission of Er3þ (Fig. 2(d)).25 Under 808 nm illumination, the transition in Nd3þ (4I9/2 / 4F5/2) occurs, followed by a nonradiative transition to the 4 F3/2. The CR between Nd3þ (4F3/2 / 4I9/2) and Yb3þ (2F7/2 / 2F5/2) initiates a spatial relay of energy to eventually excite Er3þ. On the other hand, Er3þ can also directly sensitize certain Ln3þ activators (Ln ¼ Nd3þ, Ho3þ, Tm3þ) through energy transfer process (Fig. 2(e)).37,38 In addition, Nd3þ and Er3þ are capable of intrinsic NIR-II emission, being both the sensitizer and the activator upon proper excitation (Fig. 2(f, g)). With 730, 808, or 860 nm illumination, the 4F7/2, 4F5/2, or 4F3/2 states of Nd3þ are populated, respectively; then nonradiative relaxation leads to the population of the 4F3/2 state. Eventually, electrons in the 4F3/2 state return either to 4I11/2 with the emission at 1060 nm or to 4I13/2 with the emission at 1330 nm. Similarly, the transition from 4I15/2 of Er3þ to either 4I9/2 or 4I11/2 is triggered upon excitation of 808 or 980 nm light, followed by the relaxation to the 4I13/2 state, and electrons finally return to the ground state, exhibiting emission at ~1525 nm.

Please cite this article as: Ding S et al., Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications, Journal of Rare Earths, https://doi.org/10.1016/j.jre.2020.01.021

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Table 1 Typical NIR-II emitting LnNPs in recent progress. NIR-II emitting LnNPs

Core-shell

Excitation wavelengths (nm) and transitions

b-NaYF4:50%Gd/20%Yb/2%Er b-NaLuF4:40%Gd/20%Yb/2%Er b-NaLuF4:40%Gd/20%Yb/2%Er (Ce coating) b-NaYF4:18%Yb/2%Er@NaYF4 a-NaYbF4:2%Er/2%Ce/10%Zn@NaYF4 b-NaGdF4@NaGdF4:Yb/Er(Tm, Ho)@NaYF4:

/ /(nanorod) /(nanorod) Inert shell Inert shell Active shell

980 980 980 980 980 808

b-NaLuF4:5%Nd b-NdGdF4:5% Nd@NaGdF4 b-NaYF4:7%Nd@NaYF4

/ Inert shell Inert shell

808 (Nd 4I9/2 / 4F5/2) 808 (Nd 4I9/2 / 4F5/2) 808 (Nd 4I9/2 / 4F5/2)

b-NaYF4:30%Yb/0.5%Tm/5%Nd

Active shell

808 (Nd 4I9/2 / 4F5/2)

@NaYbF4@NaYF4:30%Nd a&b-NaYF4:31%Nd/9%Yb

/

808 (Nd 4I9/2 / 4F5/2)

b-NaYF4:50%Er@NaYF4

Inert shell

b-NaYF4:Er/Tm@NaYF4

Inert shell /

808/980 (Er 4I15/2 / 4I9/2 4 I15/2 / 4I11/2) 1208 (Tm 3H62 / 3H5) 450 (Ce 2F5/22 / T2g)

(Yb 2F7/2 / 2F5/2) (Yb 2F7/2 / 2F5/2) (Yb 2F7/2 / 2F5/2) (Yb 2F7/2 / 2F5/2) (Yb 2F7/2 / 2F5/2) (Nd 4I9/2 / 4F5/2)

Yb@NaNdF4:Yb

CaS:Ce/Ln (Ln ¼ Er, Nd)

In order to obtain maximal emission intensities, the concentrations of the sensitizers and the activators need to be optimized. While too small concentrations lead to insufficient illumination, too large concentrations may quench the fluorescence. The concentration quenching effect used to be explained by cross-relaxation (CR) among the dopant ions. New evidence has shown that it is the surface defects rather than concentration quenching that decreases the luminescence.32 With an optimized core/shell structure of NaY(Er)F4@NaLuF4 to eliminate the surface defects, effective emissions were observed in 100% Er3þ doped nanoparticles. In addition to the Yb3þ, Er3þ, and Nd3þ sensitizers, our group has recently examined the effect of Tm3þ as a new sensitizer for a variety of lanthanide ions to generate NIR-II emissions.29 Under the excitation of 1208 nm, Tm3þ exhibited strong ground state absorption (GSA) from 3H6 to 3H5 and excited state absorption (ESA) from 3F4 to 3F3, which are characteristics of superior sensitizers. Then the energy harvested by Tm3þ (3H5 and 3F3) is transferred to Er3þ (4I13/2 and 4I9/2, respectively). Excited electrons in the 4I9/2 state of Er3þ fall to 4I13/2 through a two-step nonradiative transition and eventually return to the ground state 4I15/2 to emit NIR-II fluorescence at 1525 nm (Fig. 2(h)). The LnNPs are structured in a core/shell manner (NaYF4:Tm3þ,Er3þ@NaYF4). In these nanoparticles, concentrations of Er3þ (50%) and Tm3þ (5%) play important roles in acquiring the strongest NIR-II emission with core/shell structures to suppress the surface quenching effect. Moreover, by controlling the doping concentration of Tm3þ, the lifetimes of the nanoparticles can be modulated ranging from 0.36 to 4.40 ms, and realized fluorescence-lifetime imaging in the NIR-II window. Apart from being a promising sensitizer for the 1525 nm downshifting emission of Er3þ in the NIR-II region, Tm3þ could also readily sensitize Ho3þ and Yb3þ for upconverting emission at 1185 and 980 nm, respectively. Fluorides, including NaYF4 and NaGdF4, are widely employed as the host materials for LnNPs24 due to their low phonon energy and convenient structure modulation. Typically, two crystal phases dominate in these two hosts: hexagonal phase (b-phase) and cubicphase (a-phase), in which b-phase is extensively adopted because of its low phonon energies to avoid nonradiative relaxation compared with a-phase.39 However, recent efforts have shown that a-phase LnNPs can outcompete the b-phase ones in the brightness of NIR-II emission. An erbium-doped nanoparticle in a-phase

NIR-II emission wavelengths (nm) and transitions

References

1525 (Er 4I13/2 / 4I15/2) 1525 (Er 4I13/2 / 4I15/2) 1525 (Er 4I13/2 / 4I15/2) 1525 (Er 4I13/2 / 4I15/2) 1550 (Er 4I13/2 / 4I15/2) 1525 (Er 4I13/2 / 4I15/2) or 1475 (Tm 3H4 / 3F4) or 1155 (Ho 5I6 / 5I8) 1332 (Nd 4F3/2 / 4I13/2) 1064 (Nd 4F3/2 / 4I11/2) 1064/1345 (Nd 4F3/2 / 4I11/2; 4 F3/2 / 4I13/2) 1000/1345 (Nd 4F3/2 / 4I11/2; 4 F3/2 / 4I13/2) 1000/1064 (Yb 2F5/2 / 2F7/2); Nd 4F3/2 / 4I11/2 1550 (Er 4I13/2 / 4I15/2)

48

1550 (Er 4I13/2 / 4I15/2) 1540 (Er 4I13/2 / 4I15/2) or 1070/1360 (Nd 4F3/2 / 4I11/2; 4F3/2 / 4I13/2)

90 68 42 34 25

47 45 58,59

50

64

46

29 40

(a-NaYbF4:2% Er,2%Ce@NaYF4, abbreviate as a-Zn-ErNPs) has been reported to achieve a ~7.6 times more intense NIR-II emission than previously-reported b-phase nanoparticles (b-NaYbF4:2% Er,2% Ce@NaYF4, abbreviate as b-ErNPs) under 980 nm laser excitation.34 This is because in a-phase, as the CR between Yb3þ (2F5/2 / 2F7/2) and Er3þ (4I15/2 / 4I11/2) occurred, the nonradiative transition from 4 I11/2 to 4I13/2 was enhanced by the higher phonon energies (Fig. 2(c)). It was a phonon-assisted relaxation. Consequently, the downshifting emission of the 4I13/2 / 4I15/2 transition was boosted and upconversion was restrained. With Zn doping, the a-Zn-ErNPs gave another 1.5-times higher down conversion luminescence upon that of a-ErNPs with a total of ~11-fold enhancement compared with b-ErNPs and realized long lifetimes (~7.0 ms). Besides the host matrices based on fluorides (e.g. NaYF4), sulfides like CaS have also been proposed as a host material for LnNPs to achieve high fluorescence efficiency in the NIR-II window lately.40 The CaS NPs were co-doped with Ce3þ/Er3þ or Ce3þ/Nd3þ, where Ce3þ served as the sensitizer to pass the absorbed energy to Er3þ and Nd3þ to give the NIR-II emissions via the excitation by a blue light-emitting-diode (LED) chip.41 Ce3þ absorbed the 450 nm light and the electrons in ground states were populated to its T2g level, and subsequent energy transfer occurred either from T2g of Ce3þ to 2H11/2/4S3/2 of Er3þ or from T2g of Ce3þ to 4G5/2/4G7/2 of Nd3þ (Fig. 2(i)). After nonradiative and radiative transitions to 4I15/2 of Er3þ or 4F13/2 and 4F13/2 of Nd3þ, the bright NIR-II emission of Er3þ at 1540 nm or Nd3þ at 1070 and 1360 nm was observed. Based on the new host, high quantum yields (QYs) of 9.3% and 7.7% were achieved for Ce3þ/Er3þ and Ce3þ/Nd3þ co-doped CaS NPs, respectively. This new class of blue-LED-excited NIR-II nanoprobes can be used as highly responsive biosensors in in vitro bioassays. 2.2. Surface modification The surface modification of LnNPs is critical to meeting the different demands in biomedical applications. These modifications vary in functions. To be qualified for biological applications, the LnNPs have to be made hydrophilic and biocompatible. A common strategy is to encapsulate the nanoparticles with amphipathic polymers such as phospholipids and poly (acrylic acid) (PAA) to form biocompatible micelles. To ensure the stability of the LnNPs inside and to prevent aggregation, multilayer coating with cross-

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Fig. 2. (a) Schematic illustration of the core/shell structure; (b) Simplified energy transfer pathways for NIR-II emissions of Ln3þ (Ln ¼ Ho, Pr, Er, Tm) using Yb3þ as the sensitizer. The dashed curve indicates the energy transfer from Yb3þ to Tm3þ and the simultaneous two-photon ESA process of Tm3þ; (c) Simplified energyelevel diagrams depicting the energy transfer involved in a-ErNPs on 980 nm excitation. Reproduced with permission.34 Copyright 2019, Nature Publishing Group; (d) Simplified energy transfer pathways for NIR-II emissions of Er3þ using Nd3þ as the sensitizer.25 Copyright 2018, Nature Publishing Group; (e) Simplified energy transfer pathways for NIR-II emissions of Ln3þ (Ln ¼ Nd, Ho, Tm) using Er3þ as the sensitizer and the intrinsic NIR-II emissions of (f) Nd3þ and (g) Er3þ; (h) Simplified energy transfer pathways for the NIR-II emissions of Er3þ using Tm3þ as the sensitizer.29 Copyright 2019, Wiley-VCH; (i) Simplified energy pathways for the NIR-II emissions of Er3þ and Nd3þ in the Ce3þ-doped CaS nanoparticles. Reproduced with permission.40 Copyright 2019, Wiley-VCH.

linked polymers is also applied.34 Recently, graphene oxide (GO) has shown a promising coating material in maintaining the hydrophilicity. A single layer of GO can enclose the oleic acid (OA) capped LnNPs by the hydrophobic interaction between GO and OA ligands.42 This class of surface modifications is normally the foundation for further modifications. For example, the polymer layers with exposed amino groups can form covalent bonds to link other functional groups; GO encapsulation allows further modifications through non-covalent interactions.

Besides the hydrophilic and biocompatible coating, various surface modifications have been developed for specific tasks. As probes for bioimaging and diagnosis, the LnNPs have to be specifically directed to the tissue of interest. Bioactive agents, including antibodies,25,34 DNA strings,42 and viruses43 can significantly improve the selectivity of the NIR-II emitting LnNPs towards specific targets like tumors and result in higher SNRs. Meanwhile, biochemical reactions that are related to physiological abnormalities can also be exploited to direct the LnNPs. For instance, the

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overproduction of reactive oxygen species (ROS) plays an important role in inflammatory disorders44 and is used to target inflammation by redox reactions.45,46 Moreover, LnNPs with special surface modifications can perform more complicated and demanding tasks. In the cases of photothermal therapy, the LnNPs are conjugated with photothermal conversion nanomaterials like NiS2 semiconductors,47 Cu2-xS quantum dots (QD)48 and Prussian blue,49 which can absorb the NIRII emissions of the LnNPs and efficiently convert the light into heat to kill cancer cells by hyperthermia. Binding other fluorophores such as Cy7.5 to the surface of LnNPs can generate a ratiometric NIR-II probe.46 The modification with azobenzene allows dual NIR-II and photoacoustic (PA) bioimaging in vivo.50 Table 2 summarizes some of the recent progress in the application of surface-modified LnNPs. In the following sections, modifications intended for different applications and the distinct effects will be elaborated and discussed. 3. Advances in biological applications 3.1. Applications in bioimaging and biosensing Fluorescence-based bioimaging has long been appreciated as a noninvasive and non-ionizing tool for visualizing biological processes with fast feedback and high sensitivity.51e54 Compared with traditional bioimaging methods, such as computed tomography (CT)55,56 and positron emission tomography (PET),56,57 fluorescence imaging eliminates the threat of radiation exposure, and therefore, shows outstanding potential in biomedical applications. In the NIRII window, much reduced tissue autofluorescence and scattering coefficient,8 high resolution, great penetration depths (above 1 cm) and high SNR9,10 are easier to accomplish. Therefore, fluorescence imaging in the NIR-II window has become one of the frontiers of bioimaging researches. Bone imaging in the NIR-II window is rarely manageable without the liability of specific targeting ligands, but recent studies have proven that NIR-II emitting LnNPs with spontaneous affinity to the skeleton are capable of noninvasive bone imaging.58 When NIR-II emitting LnNPs (NaYF4:7%Nd@NaYF4) were coated with DSPE-mPEG (5 k Da), the resulted LnNPs@DSPE-mPEG displayed high affinity to bones in mice without any additional modification. Under the 808 nm laser excitation, the overall skeleton system, including the femur, tibia, rib and spine, was imaged with no skin

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removed (Fig. 3(a)). The LnNPs@DSPE-mPEG showed dualemission peaks at 1064 and 1345 nm, with QYs of 8.2% and 4.6% in dichloromethane (DCM), respectively. Although the QY was relatively lower, the longer emission at 1345 nm provided a much higher SNR and higher resolution due to reduced scattering and weaker autofluorescence. The bone-targeting mechanism mainly depends on the hydroxyapatite mineral binding ability of the LnNPs@DSPE-mPEG (~88%). The uptake of the nanoprobes by leukocytes (monocytes in particular) and osteoclasts might also add to the targeting effect. This insight puts forth a perspective of LnNPbased delivery in immunotherapy. In addition, NIR-II emitting LnNPs with superior optical properties can also be used to visualize the vascular and lymphatic system in vivo with high clearance efficiency. To this end, similar design as in the above bone imaging with excellent biocompatibility has been proposed.59 The NIR-II emitting LnNPs were coated with liposome made up from 1, 2-dipalmitoyl phosphatidylcholine (DPPC), cholesterol and PEGylated lipid (DSPE-PEG2000), which exhibited similar dual-emission peaks. In comparison with the prolonged retention of the bone imaging probes (in vivo half-life of ~one week), 90% of the present LnNPs@Lips could be removed from the liver within 72 h after intravenous (i. v.) administration. The LnNPs@Lips were used to detect thrombi and ischemia and to monitor ischemia perfusion (Fig. 3(b)). They also showed remarkable performance in mapping tumor vascular network and sentinel lymph nodes (SLNs). When applied in an LN dissection surgery on mice, a high SNR over 6.0 was achieved. With the guidance of NIR-II imaging, the SLN was removed precisely and quickly. Combined with other NIR-II emitting probes, LnNPs can accomplish multiplexed imaging.24,34,60 Developed by Dai's group, the aforementioned a-Zn-ErNPs34 were employed for two-plex in vivo molecular imaging in coordination with PbS quantum dots (QDs) in the NIR-II region through different excitation wavelengths and the lifetime differentiation of the nanoprobes61 (Fig. 3(c)). Moreover, with appropriate functionalization, LnNPs for multimodal imaging have been created. For instance, LnNPs functionalized with azobenzene-containing poly (acrylic acid) (LnNPs@PAAAzo) have shown excellent performance in both NIR-II fluorescence imaging and photoacoustic (PA) imaging.50 PA imaging is based on the photoacoustic (PA) effect. It refers to the generation of acoustic waves induced by the absorption of electromagnetic (EM) energy.62

Table 2 Recent progress in the application of surface-modified LnNPs. Biocompatible parts and functional groups

Applications

Stability (in solvents)

Half-lives

Excretion

References

Crosslinked polymers with PD-L1 Graphene oxide with anti-miR-21 DNA Glutathine

Bioimaging: tumor imaging

5.5 h (blood)

~90% within 2 weeks

34

2 h (blood)

e

42

Inflammation detection

7.54 min (blood)

~80% within 2 weeks

45

NiS2-EGCG

PTT

4 h (blood)

e

47

Cu2-xS QD Prussian blue

PTT PTT

e e

Not complete after 11 h Not complete after 24 h

48

PAA@Azobenzene

e

100% after 32 d

50

DSPE-mPEG

Multimodal bioimaging: NiR-II fluorescence and PA imaging Bioimaging: bone imaging

58

Bioimaging: vascular and lymphatic system imaging Tumor diagnosis PTT

20.56 min (blood); 52 h (liver); 175 h (spleen); 250 h (bone) 17.96 min (blood); 23.0 h (liver); 14.9 h (spleen) 76 min (blood) 72 min (blood)

100% after 335 h

Lipsome (DPPC/cholesterol/ DSPE-PEG2000) PAA PDA

28 d (1 PBS); 1 d (culture media, FBS) 12 h (H2O, PBS, culture media) 24 h (H2O, saline, 10% FBS, cell culture, mouse serum) 30 d (H2O, saline, 5% glucose, PBS) e 5 d (H2O, PBS, culture media) 5 d (PBS, culture media, FBS) 24 h (PBS, culture media) 25 h (PBS, culture media, plasma) 7 d (PBS, FBS) e

100% after 96 h

59

e Not complete after 7 d

68

Tumor diagnosis

49

90

Please cite this article as: Ding S et al., Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications, Journal of Rare Earths, https://doi.org/10.1016/j.jre.2020.01.021

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Fig. 3. (a) NIR-II fluorescence imaging of the skeleton. Reproduced with permission.58 Copyright 2019, American Chemical Society; (b) Schematic illustration of excretable LnNPs@Lips for multifunctional biomedical imaging and surgical navigation in the NIR-II window. Reproduced with permission.59 Copyright 2019, Wiley-VCH; (c) Schematic illustration of the two-channel setup where an 808 nm continuous-wave (CW) laser is used to excite the PbS QD and a 980 nm pulsed laser is used to excite ErNPs. Reproduced with permission.34 Copyright 2019, Nature Publishing Group; (d) Distinct lifetimes of ErNPs conjugated with three different antibodies (anti-ER, anti-PR and anti-HER2). Reproduced with permission.25 Copyright 2018, Nature Publishing Group; (e) Lifetime-resolved images for the MCF-7 and BT-474 tumors are decomposed into the three lifetime channels, represented by the red, green and blue monochromatic image sets Reproduced with permission.25 Copyright 2018, Nature Publishing Group; (f) Schematic illustration of the Tm3þsensitized LnNPs. Reproduced with permission.29 Copyright 2019, Wiley-VCH; (g) Decoded images of the two overlapping QR codes based on fluorescence-lifetime imaging. Reproduced with permission.29 Copyright 2019, Wiley-VCH. Schematic illustration of (h) the home-made TGI system and (i) fluorescence lifetime images. Reproduced with permission.64 Copyright 2019, Nature Publishing Group (j) NIR-II fluorescence images at delay times of 0, 0.4, and 0.8 ms and calculated lifetimes at different temperatures. Reproduced with permission.64 Copyright 2019, Nature Publishing Group.

Upon absorption of EM energy such as optical irradiation, transient acoustic pressure forms at the imaging agents, which become the sources of PA signals (ultrasound waves). PA imaging is to determine the spatial distribution of these agents by using ultrasonic transducers to capture these signals. In the case of the LnNPs@PAAAzo, under 808 nm laser excitation, the LnNPs (NaYF4:Yb/Nd/ Tm@NaYbF4@NaYbF4:Nd) expressed both intense downshifting emission at 1345 nm (QY ¼ 5.6%) and upconversion in blue and UV light. The upconversion emission was simultaneously absorbed by the PAA-Azo layer, which caused the Azo groups to undergo

continual photoisomerization between the cis- and trans-states reversibly.63 The PA signals (ultrasonic waves) might be generated by continual local pressure change resulted from the photoisomerization. In in vivo imaging of the femoral artery in mice, the NIR-II channel exhibited a relatively higher resolution of vessel width (497 mm) than that of the PA channel (558 mm), but the PA channel gave a twice as high SNR as that of fluorescence imaging. The PA imaging also complemented NIR-II imaging with faster feedback and greater sensitivity in deep imaging, due to less signal scattering in biological tissues.

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Even with reduced scattering and autofluorescence in comparison with traditional imaging, intensity-based NIR-II imaging still requires calibration at different observation depths because fluorescence intensity is hugely influenced by the thickness of biological tissues, especially for different wavelengths. However, the intrinsic lifetime of one fluorophore is constant regardless of penetration depth. This gives lifetime-based imaging an edge over intensity-based imaging. Our group have recently reported the lifetime-engineered NIR-II emitting LnNPs for multiplexed in vivo imaging (Fig. 3(d)).25 Lifetime tunability in the rationally designed core/multi-shell nanoprobes was realized by a systematic approach of controlled energy relay as well as a conventional doping method, which covered an unparalleled dynamic range of three orders of magnitude upon a single emission band. The results showed that the lifetimes remained consistent and could be robustly monitored at deep tissue, even though in the fluorescence mode, the SNR drops under 1.5. Based on the immunity of lifetime against the penetration depths, multiplexed quantification of MCF-7 and BT474 breast tumor biomarker (ER, PR HER2) expressions in vivo was successfully demonstrated (Fig. 3(e)), which yielded results that correlated finely with typical Western blot and immunohistochemistry tests but was noninvasive and simpler. These results may offer new views for more advanced bioimaging in deeper tissue areas. Taking the benefits in the NIR-II window, it may further improve the performance of LnNPs if the excitation wavelength is also located in the same region. To this end, our group has lately reported NIR-II excited and emitting LnNPs in vivo bioimaging and biosensing.29 In one type of these LnNPs, Tm3þ was chosen as the sensitizer (Fig. 3(f)). Under 1208 nm excitation, both the GSA (3H6 / 3H5) and the ESA (3F4 / 3F3) of Tm3þ were robust for sensitizing lanthanide activators such as Er3þ (Fig. 1(c)), Ho3þ and Yb3þ. Taking advantage of this, we designed an implantabledevice for information storage and decoding in vivo. The LnNPs were used as luminescent ink to fabricate QR codes on polydimethylsiloxane (PDMS) matrices that are known for great chemical stability and biocompatibility, and the resulted implants exhibited good flexibility. Two QR codes were made with two different lifetime levels in the same emission bands. When implanted into a mouse subcutaneously, the two QR codes were well distinguished through NIR-II TGI technology with a delay time of 0 and 6 ms, respectively. Each of them was clearly recognized and decoded by our algorithm (Fig. 3(g)). Besides bioimaging, lifetime imaging in NIR-II window has also been adopted for contactless measurements of temperature in deep biological tissues using time-gated imaging (TGI) (Fig. 3(h, i)).64 The LnNPs were made of NaYF4: Nd/Yb with the Y/Nd/Yb ratio at 60:31:9 with a mixture of a- and b-phases. At room temperature, the major emission of the LnNPs was Yb3þ (2F5/2 / 2F7/2) emission at ~ 1000 nm under excitation at 808 nm and a minor peak at 1064 nm came from Nd3þ (4F3/2 / 4I11/2). The NIR-II fluorescence lifetime decreased linearly from 470 ± 11 ms (25  C) to 390 ± 12 ms (45  C), and the calculated rate of change was 0.0096  C-1, showing great thermal sensitivity (Fig. 3(j)). The decrease was attributed to the activated Yb3þ/Nd3þenergy back-transfer process. The thermal dependence was also suspected to be related to resonant and phononassisted energy transfer and multi-phonon relaxation. When the nanoprobes were inserted into an agarose gel, which served as a biological phantom, the thermal dependence and sensitivity of NIR-II lifetime were well maintained, suggesting that water absorbance cast no effect on the NIR-II lifetime imaging. At depths ranging from 0 to 1.4 mm of meat, the rate of change in lifetime was almost constant (0.0092  C-1 ~ 0.010  C-1). The advances above have illustrated the competence of LnNPs in NIR-II bioimaging and biosensing. Not only can they target specific

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tissues of interest in vivo, but they can also be coupled with other fluorescence probes to accomplish multiplexed imaging. Besides, their tunable lifetimes are a powerful tool concerning fluorescence lifetime imaging in the NIR-II window, which suffers little from the thickness of tissues. 3.2. Applications in diagnosis The term “nanomedicine” means the application of nanotechnology to provide accurate diagnosis and effective treatment.65 As there is a growing demand for precise and noninvasive diagnosis of complicated diseases like cancer, photo-assisted nanomedicine with adjustable selectivity has attracted great attention, especially in the NIR-II window with the essentially high resolution. Among various materials, LnNPs are propitious candidates for this job in that they provide strong and stable NIR-II signals and they can be engineered with the flexibility to serve different goals. Reactive oxygen species (ROS), such as H2O2, HOCl and 1O2, play important roles in biochemical processes. The overproduction of ROS, however, usually indicates physiological abnormalities like inflammation.66,67 Lately, our group have reported some NIR-II emitting nanoprobes that can be biosensors for ROS detection in vivo with improved resolution.45,46 In one of the projects, we designed a novel ratiometric fluorescent nanoprobe by combining Er-based nanoparticles (NaY0.5Er0.5F4@NaYF4) with Cy7.5 fluorophores to detect HOCl quantitatively and accomplish highresolution imaging46 (Fig. 4(a)). The nanoparticles can be excited by both 808 nm and 980 nm to give the NIR-II emission at 1550 nm Cy7.5 was chemically conjugated to the surface of nanoparticles. Since the maximum absorption of Cy7.5 occurs at 800 nm, it spontaneously worked as a photon filter to suppress the energy absorbed by the nanoparticles when under 808 nm excitation, and therefore the NIR-II emission of Er3þ at 1550 nm (F1550Em, 808Ex) was drastically quenched. However, this 1550 nm emission was not affected (F1550Ex, 980Ex) by Cy 7.5 when excited at 980 nm since Cy7.5 showed little absorption at this wavelength. In the presence of HOCl, Cy7.5 was degraded and F1550Em, 808Ex of Er3þ recovered responsively. We used F1550Ex, 980Ex as a reference signal, and defined the response value to HOCl as the ratio of fluorescence intensities in the two channels (F1550Em, 808Ex/F1550Ex, 980Ex). The fluorescence intensity ratio rose linearly with the increased concentration of HOCl from 0 to 20 mmol/L, and the detection limit was as low as 500 nmol/L with quick feedback within less than 1 min. Besides, the ratiometric nanoprobes showed well selectivity towards HOCl rather than other types of ROS. In vivo tests also confirmed that the ratiometric nanoprobes could differentiate inflammation induced by lipopolysaccharide (LPS) from normal tissues (treated with saline) (Fig. 4(b)). In addition to the ratiometric method, an in situ assembly strategy was also developed using ultra-small NIR-II emitting LnNPs by our group to detect ROS in vivo. Glutathione (GSH) was adopted to be modified on the surface of LnNPs(NaGdF4:5% Nd@NaGdF4)45 (Fig. 4(c)). It not only formed a hydrophilic surface but also responded to the overproduction of ROS. Due to the locally excessive ROS concentration in the inflammation area, the sulfhydryl groups on GSH of the distributed LnNPs@GSH were oxidized and formed disulfide bonds among particles. Consequently, LnNPs@GSH gathered and cross-linked with one another at the inflamed areas, and became less mobile due to increased sizes. On the other hand, LnNPs@GSH in normal tissues could be excreted rapidly, thanks to the sub-10 nm ultra-small size. In mice with acute local epidermal inflammation, intense NIR-II signals at 1060 nm were observed 10 min after intravenous (i. v.) injection, demonstrating swift response (Fig. 4(d)). The SNR (~3.5) of NIR-II signals remained stable for 8 h. More importantly, less than 15% of the

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Fig. 4. (a) Schematic illustration showing the ratiometric response of [email protected] to HOCl. Reproduced with permission.46 Copyright 2019, American Chemical Society; (b) In vivo NIR-II fluorescence images and corresponding ratiometric images of LPS-treated and saline-treated mouse lymphatic drainage at different time points p. i. Reproduced with permission.46 Copyright 2019, American Chemical Society; (c) Illustration of LnNPs@GSH cross-linking at inflamed areas in response to ROS. Reproduced with permission.45 Copyright 2019, Wiley-VCH; (d) NIR-II fluorescence images of the acute local epidermal inflammation with various nanoprobes. Reproduced with permission.45 Copyright 2019, Wiley-VCH; (e) Schematic illustration of tumor-targeted NIR-II imaging with LnNPs@GO-Ab. Reproduced with permission.42 Copyright 2019, Wiley-VCH; (f)NIR-II fluorescence images of mice injected with LnNPs@GO and LnNPs@GO-Ab at different time p. i. Reproduced with permission.42 Copyright 2019, Wiley-VCH; (g) NIR-II images of CT-26 tumor mice treated with ErNPs-aPDL1 (upper), CT-26 tumor mice treated with free ErNPs (middle) and 4T1 tumor mice treated with ErNPs-aPDL1 (lower) at different time points p. i. Scale bar, 1 cm. Reproduced with permission.34 Copyright 2019, Nature Publishing Group; (h) The wide-field NIR-II images and magnified images (scale bar, 500 mm) of a CT-26 tumor mouse treated with ErNPs-aPDL1. Reproduced with permission.34 Copyright 2019, Nature Publishing Group.

injection dose of LnNPs@GSH was left in the RES two weeks after i. v. administration, confirming the biosafety of this nanoprobe. Tumor detection and cancer diagnosis are among the most popular topics in NIR-II bio-optics. Small tumor detection is critical to early cancer diagnosis. Recent advances have demonstrated that NIR-II emitting LnNPs can be used to precisely identify small tumors. For example, the recently reported NaLnF4:Gd/Yb/Er/Ce

(Ln ¼ Y, Yb, Lu) nanorods with PAA modification (LnNR@PAA) exhibited excellent performance in cancer diagnosis.68 It is noteworthy that Ce3þ doping as designed increased the 1525 nm emission of NaYbF4:Er@NaYF4 core/shell nanoparticles due to the CR between Ce3þ and Er3þ, which suppressed the upconversion pathway and accordingly enhanced the downshifting NIR-II emission.35 The LnNR@PAA expressed a superior QY of ~3.6% in water. In

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mice models, tiny metastatic tumors (~3 mm in diameter) derived from Lewis lung carcinoma (LLC) were detected under the NIR-II guidance. At 48 h post-injection (p. i.), the tumor-to-normal tissue ratio (T/N) peaked at ~16. Meanwhile, high spatial resolution (41 mm) was observed. However, the nonspecific accumulation of nanoprobes in the reticuloendothelial system (RES) still stood in the way of efficient delivery of nanoprobes to targeted sites. Due to the excellent optical and chemical properties, graphene oxide (GO) has also been used to modify the NIR-II emitting LnNPs for bioimaging applications.42 Unlike the typical ligand exchange method, GO is bound to LnNPs by the hydrophilic interaction between GO and oleic acid (OA) ligands, and forms an ultrathin layer (~1 nm) on LnNPs, which is consistent with the thickness of singlelayered GO.69e71 GO has displayed remarkable performance in biomedical applications like drug delivery and disease therapies.72e74 The unique surface properties of GO complemented the LnNPs with broad solvent dispersibility, efficient cellular uptake, outstanding biocompatibility and versatility for further functionalization. In a recent work, GO modified LnNPs (NaYF4:Yb/ Er@NaYF4) were fabricated and conjugated with anti-epithelial cellular adhesion molecule (EpCAM) antibody (LnNPs@GO-Ab) for tumor imaging in the NIR-II window (1525 nm). As EpCAM is overexpressed in MCF-7 cancer cells, it could be considered as a biomarker for MCF-7 tumors (Fig. 4(e)). In in vivo tests, LnNPs@GOAb exhibited a stronger affinity to MCF-7 tumors than plain LnNPs@GO without the antibody (Fig. 4(f)). In addition, this LnNPs@GO can also be exquisitely designed to target microRNA-21 (miR-21), a biomarker for cancer cells.75,76 Single-stranded antimiR-21 DNA, labeled with carboxyfluorescein dye (FAM), was bound to the GO surface through p-stacking interaction, and 95% of FAM fluorescence was quenched by GO at this stage.73 Once the anti-miR-21 integrated with its target (miR-21) in the cytosol and formed double-stranded DNA-RNA, it quickly detached from the LnNPs@GO, and FAM fluorescence recovered. In in vitro tests, FAM fluorescence enhanced linearly in response to the increasing miR-21 concentration and exhibited expected results in miR-21 overexpressed. The development of immunotherapy has prompted new ideas in the application of NIR-II imaging. For example, the a-Zn-ErNPs,34 as mentioned earlier, have been used to visualize immunotherapy based on the blockade of programmed cell death-1 (PD-1), an immune checkpoint.77e81 While unblocked PD-1 down-regulates the immune system and promotes tolerance towards the cancerous tissues, the blocked PD-1 triggers anti-tumor immune responses. The coupling of anti-PD-1 monoclonal antibodies (mAbs) and NIR-II nanoprobes (a-Zn-ErNPs-aPDL1) resulted in simultaneous imaging of the anti-PD-1 therapy. a-Zn-ErNPs-aPDL1 showed high sensitivity towards CT-26 (colon cancer) tumors, which are known to exhibit high PD-L1 expression, but relatively less sensitive to tumors with low PD-L1 expression due to the specific antigeneantibody reaction (Fig. 4(g and h)). In order to obtain highly biocompatible surface, they were delicately coated with four cross-linked polymer layers before the conjugation with anti-PD-L1 mAbs: hydrolyzed poly (maleic anhydride-alt-1-octadecene) (PMH), eight-arm branched polyethylene glycol amine (8-ArmPEG-NH2), poly (acrylic acid) (PAA), and mixed methoxy polyethylene glycol amine (mPEG-NH2), from inside to outside. The intense 1550 nm emission of the a-Zn-ErNPs enabled high-quality in vivo imaging. At 24h p. i., the NIR-II T/N could reach over 40.0, higher than most fluorescence-based tumor imaging. In short, NIR-II emitting LnNPs after engineering are excellent agents for photo-based diagnosis. With proper modifications, they exhibit responsiveness and sensitivity towards either inflammation or cancerous sites in vivo. The modifications, including the conjugation with other fluorophores and encapsulation of biocompatible

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and/or bioactive polymers or molecules, ensure the desired responsiveness and sensitivity as well as biosecurity. 3.3. Applications in photothermal therapy Photothermal therapy (PTT), initially based on the principle of converting photoenergy to thermal energy, causing hyperthermia in vivo and killing pathogens, is now well known for its effect on tumor necrosis.82,83 It is a noninvasive cancer treatment to first introduce PTT agents into patients and then trigger the PTT process through irradiation. Since the NIR-II window allows great penetration depths and high resolution in imaging, ideal nanoplatforms of PTT should exhibit absorbance for excitation in the NIR-II window.7 Although this kind of probes is relatively scarce right now, attempts have been made in developing therapeutic LnNPs with comparatively long excitation and emission wavelengths (NIR-II) for PTT purposes. Yu et al. reported PTT agents by coating a thin layer of Prussian blue (PB) on NdNPs (NaNdF4)49 (Fig. 5(a)). The combination lead to enhanced absorbance at 808 nm, and generated excellent photothermal effect. In addition to the intrinsic CR of Nd3þ between the 4 F3/2 / 4I15/2 and 4I9/2 / 4I15/2 states,84 the presence of PB brought about a new CR pathway (Fig. 5(b)). First, photons in PB absorbed the 808 nm light and jumped to the excited states that were within a continuous energy band. As the energy band of PB was located close to the ladder-like energy levels of Nd3þ, additional CR processes occurred when photons in the PB layer were excited by the energy released from the 4F5/2 / 4F3/2 transition of Nd3þ. Eventually, increased heat was generated owing to the strong nonradiative transition based on these two CR processes. Photons in the PB layer returned to the ground state nonradiatively, offering extra heat that added to the overall PTT effect. The photothermal conversion efficiency was as high as 60.8%. In vitro tests on HeLa cells further confirmed the superior PTT effect with illumination at 808 nm: cell viability dropped progressively with the increasing concentration of NdNPs@PB (Fig. 5(c)). On the other hand, HeLa cells incubated with NdNPs@PB but without illumination showed high and stable viability, demonstrating the low cytotoxicity of NdNPs@PB (Fig. 5(c, d)). Inorganic materials can be used as PTT agents as well. By the growth of Cu2-xS quantum dots onto the lanthanide nanorods (NaYF4: Gd/Yb/Er) in situ, the hybrid nanoprobes (LnNPs@Cu2-xS) have been developed as NIR-II/PTT multifunctional agents.48 The lanthanide nanorods were first synthesized through oleic acid (OA)-assisted hydrothermal method, which resulted in a uniform rod-like structure in the pure hexagonal phase. After that, the surface of nanorods was modified with negatively charged PAA through ligand exchange method, so that Cu2þ could be adsorbed and form the core-satellite structure (Fig. 5(e, f)). Under 808 nm excitation, the 1525 nm emission of Er3þ was observed (Fig. 5(g)), but there was noticeable quenching due to the strong NIR absorption of Cu2-xS quantum dots85 (Fig. 5(h)). The Cu2-xS quantum dots on the surface offer 32% photothermal conversion efficiency. On the model of HeLa tumor-bearing mice, the hybrid nanoprobes delineated small tumors of 5 mm in diameter in the NIR-II window with the highest SNR at ~10. Distinct tumor shrinkage proved the PTT quality of NaLnF4@Cu2-xS nanoprobes. Flower-like NiS2-coated LnNPs (LnNPs@NiS2) have been developed into a multifunctional nanoprobe for imaging, PTT and drug delivery.47 In this hybrid nanoprobes, Nd3þ doped in the LnNPs (NaLuF4:Nd) can emit 1332 nm for in vivo NIR-II imaging. The flower-like design of NiS2 (Fig. 5(i)), with a rough surface, lead to escalated scattering and reflection of photons on the surface, and thus improved absorption and photothermal conversion performance86 (Fig. 5(j)). Under 808 nm excitation, the photothermal

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Fig. 5. (a) Schematic illustration showing the PTT effect of the NdNPs@PB. Reproduced with permission.49 Copyright 2019, Wiley-VCH; (b) Illustration of the traditional NdeNd CR pathway and the new PB-Nd CR pathway. Reproduced with permission.49 Copyright 2019, Wiley-VCH; (c) Cell viability tests with and without illumination at 808 nm under different concentrations of NdNPs@PB. Reproduced with permission.49 Copyright 2019, Wiley-VCH; (d) Confocal fluorescence images of HeLa cancer cells incubated with NdNPs@PB upon 808 nm irradiation. Cells were co-stained with calcein-AM and propidium iodide (PI). Scale bar: 100 mm. Reproduced with permission.49 Copyright 2019, Wiley-VCH; (e) TEM image and (f) HRTEM image of PAA-NaYF4@Cu2xS. Reproduced with permission.48 Copyright 2019, Wiley-VCH; (g) The downshifting NIR-II emission of the NaYF4 and NaYF4@Cu2xS samples, and the inset shows the NIR-II images of the NaYF4 and NaYF4@Cu2xS solutions. Reproduced with permission.48 Copyright 2019, Wiley-VCH. (h) UVeviseNIR absorbance spectrum of pure Cu2xS QDs, NaYF4 nanorods, and NaYF4@Cu2xS nanocomposites in water. Reproduced with permission.48 Copyright 2019, Wiley-VCH. (i) TEM images and (j) photothermal images of LnNPs@NiS2. Reproduced with permission.47 Copyright 2019, American Chemical Society (k) Heating curves of mice injected with LnNPs@NiS2-EGCG under 808 nm irradiation at a power density of 2.5 W/cm2 (high laser). Reproduced with permission.47 Copyright 2019, American Chemical Society; (l) Tumor growth rates after the injection of LnNPs@NiS2 and LnNPs@NiS2-EGCG under the high laser. Reproduced with permission.47 Copyright 2019, American Chemical Society; (m) H&E histologic sections of the border of tumor and adipocytes. Reproduced with permission.47 Copyright 2019, American Chemical Society; (n) In vivo photothermal imaging of mice subcutaneous injection with PBS and NRs@PDA solution under the irradiation of 808 nm laser. Reproduced with permission.90 Copyright 2019, Ivyspring International Publisher; (O) The photographs of dissected tumors from the different groups of tumor mice at the end of PTT time. Reproduced with permission.90 Copyright 2019, Ivyspring International Publisher; (p) Relative tumor volume after treatment with PBS, NRs@PDA, Laser (control) and NRs@PDA þ 808 nm Laser irradiation. Reproduced with permission.90 Copyright 2019, Ivyspring International Publisher.

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conversion efficiency was determined to be 39.38%. The surface temperature of the tumor increased to 55  C within 7 min of irradiation with a 2.5 W/cm2 power density (Fig. 5(k)). To achieve tissue-specific PTT function, epigallocatechin gallate (EGCG), a natural heat-shock protein 90 (HSP90) inhibitor, was loaded onto the surface of LnNPs@NiS2 (LnNPs@NiS2-EGCG).87 The presence of HSP90 inhibitors enhanced PTT effect,88,89 because they impeded HSPs from assisting cancer cells to endure high temperature.11 At first, the negatively charged EGCG was adsorbed on the surface of LnNPs@NiS2 due to electrostatic forces. In the acidic environment at cancerous sites, the phenolic hydroxyl group got protonated, and the EGCG moiety was consequently released from the nanoprobe. In in vivo tests on tumor-bearing mice, LnNPs@NiS2-EGCG showed more effective tumor ablation than LnNPs@NiS2 at the same injection dose and under the same laser power (Fig. 5(l)). This means LnNPs@NiS2-EGCG allow for lower irradiation power than LnNPs@NiS2 and thus show better biocompatibility since normal tissues are likely to be damaged under high irradiation power (Fig. 5(m)). In addition, polydopamine coated NaLuF4:Gd/Yb/Er nanorods (NRs@PDA) were reported to show distinguishable PTT performance and to realize NIR-II imaging at the same time.90 Under 808 nm excitation, the photothermal conversion efficiency of NR@PDA was determined to be as high as 40.18%, superior to Au nanorods (21%)91 and Cu9S5 nanocrystals (25.7%).92 After irradiation at 808 nm for 10 min, the temperature of the mouse injected with NRs@PDA rose to ~55  C (Fig. 5(n)). Compared with other control groups, tumors in mice treated with both the NRs@PDA and the 808 nm irradiation showed significant inhibition of growth that was not observed under any other conditions (Fig. 5(o, p)), substantiating the excellent PTT efficacy.

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4. Summary and outlook Frequent advances recently have shown a considerable amount of attention and effort being put in the development of NIR-II emitting LnNPs for bio-optics. On the one hand, imaging in the NIR-II region shows high resolution and great penetration depths. On the other hand, LnNPs offer superior optical properties and biochemical adjustability. By co-doping other metal ions, LnNPs with brighter NIR-II emissions are created and their lifetimes become tunable, which is critical to fluorescence lifetime imaging. Reinventing the host matrix also results in the excellent optical performance of NIR-II emitting LnNPs. Meanwhile, innovative modifications with bioactive molecules like antibodies, DNA and RNA significantly improve the selectivity of the NIR-II emitting LnNPs towards specific in vivo targets such as the skeleton, tumors and inflamed sites, prompting better responsiveness and higher imaging resolutions. Besides, tumor detection and cancer diagnosis are still among the most discussed issues concerning NIR-II emitting LnNPs as nanoplatforms for PTT agents to improve current cancer therapy. Overall, NIR-II emitting LnNPs have shown impressive photostability and chemostability as well as remarkable optical superiority, including long photoluminescence lifetimes, low health risk and narrow emission bandwidths. Regarding the future development of LnNPs in the NIR-II window, we want to highlight some unsolved issues that are critical to further application of NIR-II emitting LnNPs: (1) There is still room to improve the optical performance of NIR-II emitting LnNPs. So far, most LnNPs used for NIR-II imaging are focused on the emission of Nd3þ (1060 and 1330 nm) and Er3þ (1525 nm) activators under NIR-I excitation (808 and/or 980 nm). However, the lack of tunability of both emission and excitation wavelengths limits the

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flexibility in application. Also, LnNPs that can be excited by long wavelengths in the NIR-II region are scarce but in need. In the discussion of LnNPs with PTT effects, it is highlighted that probes with high NIR-II absorbance are promising nanoplatforms for PTT because of the intrinsically deeper penetration and higher MPE of the NIR-II window.7 The host materials and structures that best serve the NIR-II downconversion should be investigated. In most of the current works, the matrices of NIR-II emitting LnNPs are based on the matrices of upconversion nanoparticles (UCNPs), such as NaYF4, NaGdF4, and NaYbF4, where the upconversion simultaneously competes with the downconversion in LnNPs and lowers the QY in the NIR-II region. Ce3þ doping has been reported to suppress the upconversion in such matrices but not eliminate it.35 The problem may lie in the low phonon energies in these structures. While low phonon energies benefit upconversion, properly higher phonon energy can significantly inhibit upconversion and boost NIR-II emission.34 Further studies of the role that the matrices play in the downconversion process may also be called for. Surface modifications that support the high QY of NIR-II emitting LnNPs in hydrophilic environments are needed. While the QY of NIR-II emitting LnNPs in nonpolar solutions (e.g., DCM) seems promising, the fluorescence intensity drops sharply as the materials enter hydrophilic environments. Take LnNPs doping Er3þ for example, the stretching vibration of OH groups in solutions detrimentally quench the NIR-II emissions at 1525 nm of Er3þ through a twophonon quenching mechanism because the vibration frequencies are roughly half of the 1525 nm. In order to overcome this disadvantage, surface modifications may be utilized as a screen between the NIR-II emitting LnNPs and the surrounding quenchers to protect and stabilize NIR-II emissions, improving the photo efficiency of NIR-II emitting LnNPs. NIR-II bioimaging based on LnNPs is mostly conducted in connective tissue, including bloodstreams and the lymphatic system, but not much so in nervous tissue. The development of neuroscience has generated a burgeoning demand for bioimaging technologies for neurons and brains. Therefore, NIR-II emitting LnNPs for nervous tissue imaging can be explored as one approach to neuroscience studies. Of course, these NIR-II emitting LnNPs have to maintain high biocompatibility and low cytotoxicity, in which current NIR-II emitting LnNPs still need improvement. Fluorescence lifetime imaging in the NIR-II window is a relatively new modality. It is getting rising attention, for it circumvents the problem of signal loss and distortion that happens when intensity-based imaging is carried out in deep tissues. Because the value of lifetime is not affected by the scattering of biological tissues, it can serve as a quantitative probe without the need for calibration at different depths. Nonetheless, the responsiveness of fluorescence lifetime probes is hard to control. There is still a lot to work on to create lifetime probes with excellent sensitivity and fast feedback in bioimaging. Besides refinement of the properties of NIR-II LnNPs, there are other unsettled problems regarding the application of NIR-II emitting LnNPs from bench to bedside. For instance, the synthesis of these LnNPs is limited to in-lab fabrication, but approaches for larger-scale production with high and stable reproducibility are vital to the real usage. Also, standard protocols will be needed for the appraisal of NIR-II photophysical properties, instead of the home-made equipment and individually optimized set-up.

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Acknowledgments The work was supported by the National Key R & D Program of China (2017YFA0207303), National Science Fund for Distinguished Young Scholars (21725502), Key Basic Research Program of Science and Technology Commission of Shanghai Municipality (17JC1400100) and Intergovernmental international cooperation project of Science and Technology Commission of Shanghai Municipality (19490713100).

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Please cite this article as: Ding S et al., Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications, Journal of Rare Earths, https://doi.org/10.1016/j.jre.2020.01.021