1. Introduction

Photon upconversion is a nonlinear optical phenomenon known as an anti-Stokes emission in which the sequential absorption of two or more low-energy photons leads to high-energy luminescent emission [1–3 ]. This concept was first conceived as a theoretical possibility by the Dutch-American physicist Nicolaas Bloembergen in 1959 [4]. It is known that lanthanide-doped upconversion nanoparticles (UCNPs) enable anti-Stokes emission with pump intensities several orders of magnitude lower than required by conventional nonlinear optical techniques. Therefore, starting from late 1990s, the field of UCNPs has undergone a significant expansion and become one of the most active research areas within the nanoscience community. In recent years, UCNPs has been emerging as an important class of nanomaterials owing to their wide applications in solid-state lasers, three-dimensional flat panel displays, and biolabels and bioimaging [5–9 ]. Compared with conventional biological labels, UCNPs have many advantages, including high signal-to-noise ratio without auto-fluorescence background, large anti-Stokes shifts allowing us to easily separate the photoluminescence (PL) from the excitation wavelength, narrow emission bandwidths allowing the ease of multiplexed imaging, and high resistance to photo-bleaching making them suitable for long-term repetitive imaging. Furthermore, UCNPs are non-blinking, less light scattering, and allow a deep tissue penetration because of excitation being in the near-infrared (NIR) region that is within the optical window. All these unique properties of UCNPs show their potential in biology research.

Although UCNPs have many merits, there are still some challenges. For the conventional Yb³⁺-sensitized UCNPs, 980-nm laser is the most commonly used NIR excitation source to generate upconverting luminescence. However, using a 980 nm NIR laser beam as an excitation source for biological applications has an intrinsic shortcoming: there is a high photon absorbance at about 980 nm and the absorbed light energy would transform into thermal energy, causing serious sample overheating in conjunction with substantial cell and tissue damage under continuous irradiation. Moreover, the drawback of a relatively low upconversion efficiency has hindered their extensive application. To overcome these problems, Zhan et al. reports that Yb³⁺-sensitized UCNPs could be excited by 915-nm light to minimize the overheating effect and a plasmonic dual-resonance approach was proposed to enhance the upconversion luminescence [10, 11 ]. Although these studies provide some solutions, it is still far from applications with flexibility. Therefore, it is necessary to enhance the absorption of NIR light and optimize the excitation light wavelength into an appropriate range to make UCNPs more suitable for biological applications. Compared with 980 nm laser, the use of 800 nm laser as the excitation source may both overcome the overheating issues and significantly improve the penetration depth for deep tissue imaging, since the NIR region at around 700-920 nm reaches a minimum absorbance for all bio-molecules. Thus Nd³⁺ ions could become a quite potential candidate as the sensitizer to realize the upconverting luminescence of UCNPs, due to the intense absorption cross-section of Nd³⁺ around 800 nm and efficient energy transfer from excited Nd³⁺ to Yb³⁺ ions.

In this review paper, we focus on controlling the excitation of upconverting luminescence by utilizing Nd³⁺-sensitized UCNPs in lanthanide-doped nanoparticles and recent experimental progress in using Nd³⁺-sensitized nanomaterials in many areas. We start with a brief introduction to nanocomposition and mechanisms of Nd³⁺-sensitized UCNPs. Next, we give a more detailed description of typical nanostructures of Nd³⁺-sensitized UCNPs. Furthermore, an important emphasis is placed on applications including downconversion and upconversion photoluminescence for bioimaging, high-resolution and deep tissue imaging and tumor diagnosis and therapy. We hope that researchers in optical bioimaging and related biological fields can benefit from this review.

2. Composition and construction

2.1 Nanocomposition and cascade-pumped mechanism

In contrast to commonly used organic fluorophores and quantum dots, UCNP consists of a crystalline host and a dopant (usually lanthanide ions) added in a low concentration. The host lattice provides a matrix for the dopant with its crystal structure while the dopant provides luminescent centers. For efficient upconversion to proceed, physically existent intermediate states between the ground state and the emitting state are required to act as energy reservoirs. The lanthanides’ $4f^n$ electronic configurations are split by appreciable electronic repulsion and spin–orbit coupling, resulting in a rich energy-level pattern which makes lanthanides ideal candidates for achieving photon upconversion [12]. The trivalent ions may be doped in different host materials, varying from fluorides to oxides dependent on the synthesis procedures and applications [13–19 ]. Fluorides, particularly sodium rare-earth (RE) fluorides (NaREF4), have been proven to be the most efficient host materials for upconversion luminescence since their intrinsic low phonon energies can greatly decrease the nonradiative relaxation probability and thus enable high upconversion efficiency [20–23 ].

Lanthanide ions with a ladder-like energy level structure are suitable for the single doping system including Er³⁺, Tm³⁺, and Ho³⁺, which are frequently used as activators of UCNPs. In single doping nanocrystals, quenching of excitation energy resulting from high doping levels caused deleterious cross-relaxation and low pump efficiency resulting from low absorption cross-sections of most lanthanide activator ions response for relatively low upconversion efficiency. To increase the absorption of lanthanide-doped UCNPs, sensitizers (e.g., Yb³⁺) are often additionally doped along with activator, which should strongly absorb excitation energy and ensure efficient energy transfer to the activator.

In contrast to Yb³⁺-sensitized (excited by 980 nm NIR laser) UCNPs, Nd³⁺-sensitized (excited by 800 nm NIR laser) UCNPs have many advantages that they may significantly improve the penetration depth and overcome the overheating effect due to water absorption under 980 nm excitation. Besides, Nd³⁺ has very large absorption cross-section around 800 nm and energy transfer from excited Nd³⁺ to Yb³⁺ ions is very efficient [24–26 ]. According to above merits, Nd³⁺ ions could become a promising alternative as the sensitizer to extend UCNPs applications. The Nd³⁺-sensitized UCNPs commonly tri-doped with Nd³⁺, Yb³⁺ and Ln³⁺ (activators). The cascade-pumped mechanism of Nd³⁺-sensitized UCNPs can be simply illustrated with Fig. 1 . The sensitizer Nd³⁺ absorbs the excitation energy and efficiently transfers the energy to the activator Ln³⁺ (Er³⁺, Tm³⁺, and Ho³⁺) via the energy transfer (ET) bridging ion Yb³⁺, following with photon emissions. A nearly 90% efficiency was observed for energy transfer between the Nd^{3+ 4}F_3/2 and Yb^{3+ 2}F_5/2 states [27]. The use of Nd³⁺ ions as sensitizers facilitates the energy transfer and photon upconversion of a series of lanthanide activators (Er³⁺, Tm³⁺, and Ho³⁺) at a biocompatible excitation wavelength (800 nm) and also significantly minimizes the overheating problem associated with 980 nm excitation.

 

Fig. 1 Schematic mechanism of cascade-pumped process.

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2.2. Structure constructing

With the development of nanotechnology, a variety of chemical techniques, including coprecipitation, sol–gel processing, combustion synthesis, thermal decomposition and hydro(solvo)-thermal synthesis, have been demonstrated to synthesize lanthanide-doped UC nanocrystals [28]. According to the recent work on Nd³⁺ doped UCNPs, thermal decomposition [24, 26, 29 ] and coprecipitation [27, 30, 31 ] has become the most commonly used routes to the synthesis of high quality Nd³⁺-sensitized UCNPs. Except from lanthanide-doped core-singly structured UCNPs, plenty of progress has also been made in the design and synthesis of UCNPs with core@shell structures in the past decade. The core@shell structures now are frequently used for enhancing energy transfer efficency within UCNPs. For the first time the intrinsic excitation wavelength of colloidal dispersible UCNPs was engineered by Han et al. according to the fabrication of Nd/Yb/Er (Tm) tri-doped core@shell β-NaYF₄ colloidal UCNPs [24]. However, the doping concentration of Nd³⁺ in the tri-doping system must be constrained to a very low level (less than 1%) to minimize the quenching of the excitation energy via efficient energy back transfer from activators to Nd³⁺. Therefore, directly codoping Nd³⁺ into Yb³⁺/Er³⁺ UCNPs always lead to lower upconversion luminescence (UCL) under 800 nm irradiation than that under 980 nm irradiation.

To solve this issue, great progress has been achieved with a core@shell structure that separates the activator and sensitizer Nd³⁺ into core and shell layers, respectively. Xie et al. described a novel type of NaYF₄:Yb,Nd,A@NaYF₄:Nd (A = Tm, Er, Ho) core@shell UCNPs which spatially confined the doping of Nd³⁺ and made it can be effectively excited at 795 nm, as shown in Fig. 2(a) [27]. Significantly, this structure, with high-concentration doping of Nd³⁺ (~20%) in the shell layer, markedly enhanced the UCL by ca. 7 times compared with triply doped NaYF₄:Yb,Er,Nd@NaYF₄ UCNPs under 800 nm excitation. Similarly, to address the spatial separation of Nd³⁺ and the activator, the Yan group also synthesized β-NaGdF₄:Yb,Er@NaGdF₄:Nd core@shell nanoparticles, which could achieve high upconversion excitation efficiency with a greatly minimized tissue overheating effect [29].

 

Fig. 2 (a) Schematic design (top) and simplified energy level diagram (bottom) of a core@shell nanoparticle for photon upconversion under 800 nm excitation. Nd³⁺ ions doped in the core and shell layers serve as sensitizers to absorb the excitation energy and subsequently transfer it to Yb³⁺ ions. After energy migration from the Yb³⁺ ions to activator ions, activator emission is achieved via the Nd³⁺-sensitization process [27]. (b) Schematic illustration of the proposed energy-transfer mechanisms in the quenching-shield sandwich-structured UCNPs upon 800 nm excitation. Proposed energy-transfer mechanisms in the quenching-shield sandwich nanoparticle upon 800 nm diode-laser excitation [26]. (c) Schematic design of the active-core@active-shell nanoparticle architecture for photon upconversion upon 808 nm laser excitation. Nd³⁺ and Yb³⁺ ions are simultaneously codoped in both the core and shell layers, and act as cosensitizers to absorb the excitation energy and subsequently transfer it to the Ln³⁺ activator ions, giving rising to upconverted emissions. Schematic illustration of the energy-transfer mechanism in the active-core@active-shell nanoparticles [31] (Reprinted with permission from [26, 27, 31 ]).

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However, in this optimized core@shell structure there still exists the problem of the energy back transfer from activators to the sensitizer Nd³⁺, which directly deactivates the activators as well as restricts the harvest enhancement of NIR excitation light by increasing the Nd³⁺ concentration in the shell layer. To address this issue, Zhong et al. have proposed a quenching-shield sandwich structure (NaYF₄:Yb,Er@NaYF₄:Yb@NaNdF₄:Yb) to eliminate the deleterious cross-relaxation pathways between the activator and sensitizer for 800 nm excited UCL of Nd³⁺ sensitized nanoparticles, as shown in Fig. 2(b) [26]. This well-defined unique nanostructure is essential to eliminate the deleterious cross-relaxation pathways between the activator and sensitizer by means of a precisely controlled transition layer. By optimizing the thickness of the interlayer, the emission intensity of the quenching-shield sandwich structure upon 800 nm excitation reaches a maximum when the interlayer thickness is controlled at about 1.45 nm, and is even brighter than conventional 980 nm-excited nanoparticles at low excitation power density (0.5 W cm^–2), as a result of the increased sensitizer concentration induced higher absorption cross-section of the sensitizer. Huang et al. proposed the active-core@active-shell nanostructured design to achieve a maximum 522-fold enhancement in activator emission intensity of Nd³⁺/Yb³⁺-based upconversion nanoparticles upon excitation at 808 nm, as shown in Fig. 2(c). The active-shell design has greatly enhanced near-infrared absorption at around 808 nm with minimized deleterious cross-relaxation, and efficiently delivered the absorbed near-infrared radiation from Nd³⁺ ions to the luminescent core via Yb³⁺ ions as bridging sensitizers [31].

The core@shell structures, not only can be used for nanoparticles with enhanced energy transfer efficency, but also can be adopted to realize fine tuning of the emission color. Wen et al. fabricated a novel design, based on nanostructural engineering to separate the unwanted electronic transitions for constructing a new class of materials displaying tunable upconversion emissions spanning from ultraviolet (UV) to the visible spectral region by single wavelength excitation at 808 nm [32]. As shown in Fig. 3(a-c) , most of the as-prepared Nd³⁺-sensitized UCNPs exhibit intensive green/blue emission spectra, which would reduce the penetration depth caused by the strong reabsorption of green/blue light in biological tissue [25]. Recently, Chen et al. developed specially designed NaGdF₄:Yb/Ho/Ce@NaYF₄:Yb/Nd active-core@active-shell nanoarchitecture to achieve 808 nm excited single-band red upconversion luminescence of Ho³⁺, as shown in Fig. 3(d) [30]. Nevertheless, Nd³⁺-sensitized single-band red UCNPs still need for optimization since the upconversion luminescence efficiency of Ho³⁺-activated UCNPs is commonly lower than that of Er³⁺-activated UCNPs [33]. Upconversion luminescence (especially red emission) and red to green upconversion intensity ratio can be remarkably enhanced or tuned by Mn²⁺ doping [34–36 ]. Zhao and associates manipulate green and sing-band red UCL in hexagonal NaYF₄:Yb/Er NPs by controlling the Mn²⁺ content [37]. By contrast, Wang et al. developed another strategy to generate pure single-band red UC emssions, which was mainly based on the employ of KMnF₃ as host materials with Ln³⁺ (Yb/Er, Yb/Ho) dopants homogeneously incorporated into the host lattice [38]. These works show the possibility of achieving more efficient 808 nm excited single-band red UCL in Nd³⁺/Yb³⁺/Er³⁺ co-doped UCNPs that contain Mn²⁺ ions, as a result of the efficient energy transfer between Mn²⁺ and doped Ln³⁺ ions. These results demonstrate that core@shell structures can be exploited to integrate and coordinate several distinct optical processes for achieving unusual upconversion of NIR light in the medical spectral window (about 800 nm) into tunable emissions spanning from UV to the visible spectral region.

 

Fig. 3 The upconverting emission spectra of (a) β-NaYF₄:(0–5%)Nd,20%Yb,2%Er/NaYF₄ and (b) β-NaYF₄:(0–3%)Nd,30%Yb,0.5%Tm/NaYF₄ UCNPs. The upconverting luminescent pictures were inserted in (a, b) with the laser path labeled [24]. (c) Room-temperature upconversion luminescence spectra of ErCSS nanoparticles dispersed in water and cyclohexane (0.5 W/cm² 800-nm excitation), ErCS nanoparticles dispersed in water and cyclohexane (0.5 W/cm² 980-nm excitation) with the same concentration (1mg/ml). Upconversion luminescence photograph of ErCSS nanoparticles dispersed in water and cyclohexane [26]. (d) A schematic diagram to achieve 808 nm excited single-band red upconversion luminescence by synthesized Yb/Ho/Ce:NaGdF₄@Yb/Nd:NaYF₄ active-core@active-shell nanoparticles (inset: schematic active-core@active-shell structure and energy level diagrams of nanoparticle) [30] (Reprinted with permission from [24, 26, 30 ]).

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3. Application

Due to their featured properties, minimized overheating effect and improvement of the penetration depth, Nd³⁺-sensitized UCNPs hold larger potential for practical applications, particularly in the realm of bioapplications, such as tissue sensing, imaging and cancer therapy. Therefore, in this section we would discuss the applications of Nd³⁺-sensitized UCNPs, mainly including down/up-conversion photoluminescence for bioimaging, high-resolution microscopic and deep tissue imaging, tumor diagnosis and therapy.

3.1 Downconversion and upconversion photoluminescence for bioimaging

In recent years, photoluminescence imaging has become an important technique used in biomedical research application. Photoluminescence imaging can be divided into downconversion and upconversion imaging. It is noted that the Nd³⁺ ion is considered as a good candidate for downconversion and upconversion imaging, due to its abundant ladder-like energy states, large absorption cross-section around 800 nm. Therefore, the two kinds of bioimaging techniques can be achieved simultaneously by introducing Nd³⁺ ion. Although Nd³⁺-sensitized UCNPs were utilized to achieve upconversion imaging, beginning with 2013, some studies on Nd³⁺ based downconversion imaging were reported earlier [39–41 ]. For example, Chen et al. reported that near-infrared to near-infrared (NIR-to-NIR) downconversion photoluminescence peaked at∼900, ∼1050, and∼1300 nm was achieved by taking advantage of synthesized core@shell NaGdF₄:Nd³⁺/NaGdF₄ nanocrystals, as shown in Fig. 4(a) [40]. In addition, NIR-to-NIR PL bioimaging was demonstrated both in vitro and in vivo through visualization of the NIR-to-NIR PL at ∼900 nm under 740 nm excitation, as shown in Fig. 4(b) and (c) [40]. It was noted that authors subcutaneously injected a nude mouse using 200 μL of 2 mg/mL core@shell NaGdF₄:Nd³⁺/NaGdF₄ nanoparticles with an injection depth of about 3 mm, for in vivo bioimaging. The fact that both excitation and the PL of these nanocrystals are in the biological window of optical transparency, combined with their high quantum efficiency, spectral sharpness, and photostability, makes these nanocrystals extremely promising as optical bioimaging probes.

 

Fig. 4 (a) The schematic diagram of core@shell NaGdF₄:Nd³⁺/NaGdF₄ nanocrystals under 740 nm excitation, (b) PL images of HeLa cells treated with ligand-free (NaGdF₄:3% Nd³⁺)/NaGdF₄ nanoparticles. Inset shows localized PL spectra taken from cells (red) and background (black), (c) superimposed image (bright field nude mouse image and spectrally unmixed PL image) [40]. (d) The schematic diagram of Nd³⁺/Yb³⁺ co-doped shell, (e) and (f) UC imaging of a nude mouse subcutaneously injected with Er@Nd NPs in vivo. The images were obtained with 980 nm laser (e) and 808 nm laser (f) irradiation, both with a power density of 200 mW/cm². ROIs are denoted in black dot circles. Insert images were infrared thermal image of a nude mouse during continuous (e) 980 nm laser irradiation for 50s and (f) 808 nm laser irradiation for 300s [29] (Reprinted with permission from [29, 40 ]).

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In addition to downconverting imaging, upconverting imaging technique has recently attracted great research interest for background free imaging and its extensive biological application in vitro and in vivo, benefiting from the large tissue penetration depth of near-infrared excitation light. Nd³⁺ ion was introduced as the sensitizer to achieve upconversion imaging [29, 42 ]. In contrast to Yb³⁺-sensitized UCNPs, Nd³⁺-sensitized UCNPs have potential merits in bioimaging. For example, Wang et al. reported that Nd³⁺ ion was introduced as the sensitizer to achieve upconversion imaging in vivo and authors built a core@shell structure to ensure successive Nd³⁺-Yb³⁺-activator energy transfer, as shown in Fig. 4(d) [29]. In addition, they injected Nd³⁺-sensitized UCNPs into a nude mouse (20 mg/mL, 50μL) and demonstrated that Nd³⁺-sensitized UCNPs can be used in vivo imaging. Their experiment results confirmed that the laser-induced local overheating effect is greatly minimized. Typical images were shown in Fig. 4(e) and 4(f) with irradiation of 808 and 980 nm laser [29]. Numbers of photons emitted from the same region of interest (ROI) were found to be comparable ($6.3\times {10}^9$for 808 nm excitation and $5.6\times {10}^9$for 980 nm). This implies that 808 nm laser excitation is efficient for in vivo applications of Nd³⁺-sensitized UCNPs. At the same time, the insert images indicated that local overheating effect is minimized under 808 nm excitation. Furthermore, with the development of nanoscience, intense up- and down-conversion luminescence were successfully achieved in well designed and synthesized core@shell structured Nd³⁺-sensitized nanoparticles simultaneously under 808 nm continuous-wave laser excitation, as reported by Zhang group [43]. Therefore, Nd³⁺-sensitized UCNPs would play a more important role in vivo upconversion and downconversion imaging.

3.2 Deep tissue and high-resolution imaging

According to relative researches, Nd³⁺-sensitized UCNPs have exhibited unique potential for use in deep biological tissue imaging. Because Yb³⁺- sensitized UCNPs are excited at 975 nm causing relatively high absorption in tissue and the intensity of 975 nm laser beam would overwhelmingly attenuated while diffusing in biological tissues, resulting in a limited penetration ability. However, the tissue absorption is lower by exciting Nd³⁺- sensitized UCNPs at 800 nm excitation band. Andersson-Engels group experimentally and theoretically quantify to what extent Nd³⁺-sensitized UCNPs will provide an increased signal at larger depths in tissue compared to conventional 975-nm excited Yb³⁺- sensitized UCNPs [44]. As shown in Fig. 5(a) and (b) , the signal as a function of sample depth is plotted for the two types of UCNPs. The signals are plotted in linear and semilogarithmic scales to clearly visualize the gain in signal for the Nd³⁺- sensitized UCNPs. The comparison of the two different particle signals as a function of depth yields significant improvement in the emission signal intensity for the Nd³⁺- sensitized UCNPs.

 

Fig. 5 (a)-(b) Depth measurements of Yb³⁺/Tm³⁺ and Nd³⁺/Yb³⁺/Er³⁺: (a) a linear scale, and (c) a plot in semilogarithmic scale [44], (c)-(d) Multiphoton imaging of (c) 795-nm-excited UCNP (Inset: the SEM image of single UCNP on the coverslip) and (d) 975-nm-excited UCNP [25], (Reprinted with permission from [25, 44 ]).

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In recent development, UCNPs have been proven valuable as luminescent probes in the advancement of biological imaging with substantially improved spatial resolution. According to the equation$\Delta x\Delta y\approx 1.22\lambda /2NA{\left(n\right)}^{1/2}$, compared with Yb³⁺- sensitized UCNPs under 975-nm excitation, Nd³⁺- sensitized UCNPs under 800-nm-excitation could effectively improve multiphoton microscopy (MPM) resolution. Our group demonstrated that the resolution can be improved by utilizing 795-nm light excited Nd³⁺- sensitized UCNPs. The images and the full width at half maximums (FWHMs) analysis by fitting the emission profiles are shown in Fig. 5(c) and (d). Experimental FWHMs of 795 nm and 975 nm excitation were calculated as the value of 345 nm and 425 nm, respectively, in good agreement with the theoretical values (342 nm and 420 nm). It was noted that the FWHM in the case of 795 nm excitation is 20% smaller than that of the 975 nm excitation [25]. With the optimization of materials and wavelength, our group also proposed visible-to-visible four-photon ultrahigh resolution microscopic imaging by using a common cost-effective 730-nm laser diode to excite the prepared Nd³⁺- sensitized UCNPs [45]. The lateral imaging resolution as high as 161-nm was achieved via the four-photon upconversion process, as shown in Fig. 6(a) . What is more, a sample with fine structure was imaged to demonstrate the advantages of visible-to-visible four-photon ultrahigh resolution microscopic imaging with 730-nm diode laser excited Nd³⁺- sensitized UCNPs, as shown in Fig. 6(b)-(f).

 

Fig. 6 (a) Gaussian fitting of four-photon fluorescence spot, FWHM_IPSF = 161 nm (inset: the SEM image of a single Nd³⁺-UCNP sample and four-photon fluorescence imaging of a single Nd³⁺-UCNP). (b) UC fluorescence image of Nd³⁺-UCNPs (inset: bright field image), (d)-(f) the corresponding line-scanning profile from the image shown in (c) showing FWHM = 168 nm (730-nm/four-photon); FWHM = 250 nm (730-nm/two-photon); FWHM = 360 nm (980-nm/two-photon) (Reprinted with permission from [45]).

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3.3 Tumor diagnosis and therapy

UCNPs not only provided potential application in bioimaging, but also were used in tumor diagnosis and therapy. Conventional UCNP-based photodynamic therapy (PDT) system, however, utilized excitation at 980 nm, at which water has significant absorption, leading to overheating effect. Therefore, Nd³⁺-sensitized UCNPs provide potential advantages for PDT under 800-nm band excitation. For example, Wang et al. firstly designed the NaYF₄:Yb/Ho@NaYF₄:Nd@NaYF₄ core@shell@shell nanostructure, as shown in Fig. 7(a) [46]. The optimal structure was utilized for photodynamic therapy and simultaneous fluorescence imaging of Hela cell triggered by 808 nm light, where low heating and high PDT efficacy were reached. At the same time, Zhu et al. also reported an efficient nanoplatform using 808-nm excited NaYbF₄:Nd@NaGdF₄:Yb/Er@NaGdF₄ core@shell@shell nanoparticles loaded with Chlorin e6 and folic acid for simultaneous imaging and PDT [47].

 

Fig. 7 (a) The schematic diagram of the nanoplatform for photodynamic therapy and imaging [46], (b) Functionalization of core@shell@shell nanoparticles with photosensitizer Ce6, PEG, and cancer-targeting moiety folic acid (FA) for simultaneous imaging and PDT [47], (c) Photographs of excised tumors from euthanized mice, (d) Images of representative group [49] (Reprinted with permission from [46, 47, 49 ]).

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Apart from that Nd³⁺-sensitized UCNPs were used in PDT, they were also utilized in in photothermal therapy [16, 48 ] and tumor diagnosis and drug deliver [18, 49 ]. For photothermal therapy, Xu et al. proposed that multifunctional nanoparticles based on the Nd³⁺/Yb³⁺ co-doped NaYF₄ could simultaneously act as the luminescent nanothermometers and nanoheaters and find potential application in photothermal therapy [48]. In tumor diagnosis and drug deliver, Lin group designed and synthesized core@shell structured Nd³⁺-sensitized NaYF₄:Yb/Nd/Er@NaYF₄:Nd@mSiO₂ nanoparticles [49]. The core imparts the nanomaterials with luminescence properties for upconversion optical imaging under 808 nm laser irradiation, whereas the mesoporous SiO₂ shell allows the nanomaterials to be loaded with anticancer drug doxorubicin (DOX). The therapeutic efficacy of the DOX-loaded NPs in vivo was proved to be greater than pure DOX and saline as a control. As shown in Fig. 7(c), the tumor sizes of DOX-NPs groups were visibly smaller than those of DOX and control groups, which means DOX-NPs have great therapeutic efficacy. The control group and DOX-NPs group were shown in Fig. 7(d). However, DOX group was not shown due to the layout of the picture. Therefore, the above performances indicate that Nd³⁺-sensitized UCNPs show multifunctionality including PDT, tumor diagnosis and drug deliver.

4. Discussions and conclusion

Although the Nd³⁺-sensitized UCNPs have attracted a great deal of attention in many fields due to their unique optical and chemical properties, there are still many challenges for the development of Nd³⁺-sensitized UCNPs. Firstly, the emission intensity and spectra of Nd³⁺-sensitized UCNPs are still unsatisfactory, which need enhancing the quantum yield [11] and tuning the emission wavelength by delicate designing and optimizing the structure of the Nd³⁺-sensitized UCNPs. Through the development of Nd³⁺-sensitized UCNPs, the structure, especially the core@shell structure, becomes more and more complicated, indicating that the traditional synthesis approach hardly meets the practical needs. Thus, the second prospects is to develop new synthesis method which can fulfill the requirements for the fabrication of complicated multi-layer structured Nd³⁺-sensitized UCNPs. In addition, notable advances have occurred in the synthesis and multifunctionalization of Nd³⁺-sensitized UCNPs, but it is still hard to understand the complex processes in biological systems, such as non-specific binding and loss of biological activities at the bio/nano interface, especially under physiological conditions. Last but not the least, according to the previous reports, fluoride ions of higher dose have stronger toxicity [50–52 ]. However, for the upconversion nanoparticles, fluoride exists in the form of nanoparticles compound and there are many reports that demonstrated low toxicity of upconversion nanoparticles in vitro and vivo experiment. Certainly, we can’t neglect the fact that there are no reports that confirmed the effect of fluorine concentration of upconversion nanoparticles. So, for upconversion nanoparticles, the fluorine toxicity and nanoparticles toxicity for bioapplication should also be investigated and estimated order to quantify or predict potential adverse effects on human or environment in future study. Therefore, new advancements in diverse aspects are needed to make rapid progress in this field to fulfill requirements of the practical applications.

In this review, recent progresses of Nd³⁺-sensitized UCNPs were summarized, including nanocomposition, mechanisms and some typical nanostructures. In addition, an important emphasis was placed on applications including downconversion and upconversion photoluminescence for bioimaging, high-resolution and deep tissue imaging and tumor diagnosis and therapy. We hope this review can also provide a scientific reference to biomedical and chemical researchers who are working in the development of nanoprobes.