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X-ray-activated persistent luminescence nanomaterials for NIR-II imaging

Abstract

Persistent luminescence is not affected by background autofluorescence, and thus holds the promise of high-contrast bioimaging. However, at present, persistent luminescent materials for in vivo imaging are mainly bulk crystals characterized by a non-uniform size and morphology, inaccessible core–shell structures and short emission wavelengths. Here we report a series of X-ray-activated, lanthanide-doped nanoparticles with an extended emission lifetime in the second near-infrared window (NIR-II, 1,000–1,700 nm). Core–shell engineering enables a tunable NIR-II persistent luminescence, which outperforms NIR-II fluorescence in signal-to-noise ratios and the accuracy of in vivo multiplexed encoding and multilevel encryption, as well as in resolving mouse abdominal vessels, tumours and ureters in deep tissue (~2–4 mm), with up to fourfold higher signal-to-noise ratios and a threefold greater sharpness. These rationally designed nanoparticles also allow the high-contrast multiplexed imaging of viscera and multimodal NIR-II persistent luminescence–magnetic resonance–positron emission tomography imaging of murine tumours.

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Fig. 1: X-ray-activated PL from Ln-PLNPs.
Fig. 2: Controlled structures and compositions of Ln-PLNPs for NIR-II PL investigation.
Fig. 3: NIR-II PL multiplexed encoding with multilayered PLNPs.
Fig. 4: X-ray-activated Ln-PLNPs for in vivo high-contrast PL imaging.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

The code that has been used for this work is available from the corresponding author upon request.

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Acknowledgements

F.Z. and D.Z. acknowledge support from the National Key R&D Program of China (grant no. 2017YFA0207303). F.Z. and D.Z. acknowledge support from the National Natural Science Foundation of China (NSFC, grant nos 22088101 and 51961145403). F.Z. acknowledges support by the National Natural Science Foundation of China (NSFC, grant no. 21725502) and the Research Program of Science and Technology Commission of Shanghai Municipality (grant no. 20JC1411700). Y.F. acknowledges support from the National Natural Science Foundation of China (grant no. 21904023) and the Research Program of Science and Technology Commission of Shanghai Municipality (grant no. 19490713100), Y.Y. acknowledges support from the National Natural Science Foundation of China (grant no. 11974097) and H.Z. acknowledges support from the Research Program of Science and Technology Commission of Shanghai Municipality (grant no. 20490710600).

Author information

Authors and Affiliations

Authors

Contributions

F.Z., Y.F. and Y.Y. conceived and designed experiments. P.P. synthesized the nanoparticles and conducted the PL coding experiments. Y.C. and P.P. conducted the imaging of the blood vessels, ureters and tumours. P.P. and C.S. conducted the dual-channel imaging of the organs and multimodel tumour imaging. H.Z., Y.F. and P.P. built the NIR-II imaging system. Xuan Liu and L.L. developed the codes for image processing. P.P., F.Z. and Y.F. wrote the manuscript. F.Z., Y.F., Y.Y., P.P., Xiaogang Liu, M.Z. and H.Z. analysed the results, figures and supplementary information. F.Z., Y.F., Y.Y., P.P., Xiaogang Liu and D.Z. discussed the mechanism of PL in these Ln-based nanoparticles. D.Z. and F.Z. also contributed to the discussions about the experimental approaches to imaging of the blood vessels and ureters. All the authors contributed to discussing and editing the manuscript.

Corresponding authors

Correspondence to Yong Fan, Yanmin Yang or Fan Zhang.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Cyrille Richard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Influence of the excitation light on the persistent luminescence of Ln-PLNPs.

a, NIR-II PL images of Er-PLNPs (NaYF4:3%Er@NaYF4), Nd-PLNPs (NaYF4:1%Nd@NaYF4), Ho-PLNPs (NaYF4:1%Ho@NaYF4) and Tm-PLNPs (NaYF4:1%Tm@NaYF4) after being pre-irradiated with UV light (254 nm and 365 nm, 6 W for 10 min irradiation) or X-rays (~200 Gy). b, the corresponding intensity profiles of NIR-II PL images in a. Due to the large bandgap of fluoride hosts of Ln-PLNPs, high-energy X-rays are necessary to generate persistent luminescence in the NIR-II window.

Extended Data Fig. 2 Persistent luminescence images of various Ln-PLNPs in the visible-NIR region.

a, PL images of centrifuge tubes, filled with hexagonal Er-PLNPs (NaYF4:3%Er@NaYF4), Nd-PLNPs (NaYF4:1%Nd@NaYF4), Ho-PLNPs (NaYF4:1%Ho@NaYF4), and Tm-PLNPs (NaYF4:1%Tm@NaYF4), recorded at different emission bands. b, c, d, Corresponding long-lasting properties of Er-PLNPs, Nd-PLNPs, Ho-PLNPs, and Tm-PLNPs in the VIS emission bands (b), and NIR-II emission bands (c, d) shown in a. bg: background, ROI: region of interest. e, Corresponding NIR-II PL signal intensities of Er-PLNPs, Nd-PLNPs, Ho-PLNPs, and Tm-PLNPs shown in d (n = the number of pixels within the corresponding ROI). Imaging exposure time for VIS and NIR-II images are 1 s and 5 s, respectively. The data are shown as the mean ± s.d.

Source data

Extended Data Fig. 3 Comparison of the influence of crystal phase on NIR-II persistent luminescence.

a, TEM images of cubic and hexagonal Er-PLNPs with core (NaYF4:3%Er) and core-shell (NaYF4:3%Er@NaYF4) structures. b, XRD pattern of cubic and hexagonal core-shell Er-PLNPs. The standard diffraction patterns of hexagonal NaErF4 (JCPDS 27–0689), hexagonal NaYF4 (JCPDS 27–1427), cubic NaErF4 (JCPDS 27–0688) and cubic NaYF4 (JCPDS 27–1428) are included for references. c, Corresponding NIR-II PL decay curves of cubic and hexagonal Er-PLNPs with bare core and core-shell structure. NIR-II PL signals of hexagonal NaYF4:3%Er@NaYF4 were about 13, 20, and 23 times higher than that of cubic NaYF4:3%Er@NaYF4 at 10 min, 30 min, and 50 min, respectively, probably due to a reduced level of crystal defects or internal quenching. Decay curves were abstracted from corresponding NIR-II PL images with 5 s exposure time.

Source data

Extended Data Fig. 4 Influence of storage temperature on the NIR-II persistent luminescence of Er-PLNPs (NaYF4:3%Er@NaYF4) and Nd-PLNPs (NaYF4:1%Nd@NaYF4).

a, Storable NIR-II PL of Er-PLNPs (0.2 mM in cyclohexane) at room temperature and −20 oC as a function of time. b, Storable NIR-II PL of Er-PLNPs and Nd-PLNPs powders (0.2 mM) stored at −20 oC as a function of time. n = 3 independent experiments. NIR-II PL signals were abstracted from corresponding images with 5 s exposure time. The data are shown as the mean ± s.d.

Source data

Extended Data Fig. 5 Persistent luminescence properties of Ln-PLNPs with Yb3+, Pr3+, Tb3+, Dy3+ and Sm3+ as the activators.

a, TEM images of Yb-PLNPs (NaYF4:1%Yb@NaYF4), Pr-PLNPs (NaYF4:1%Pr@NaYF4), Tb-PLNPs (NaYF4:1%Tb@NaYF4), Dy-PLNPs (NaYF4:10%Tb@NaYF4) and Sm-PLNPs (NaYF4:1%Sm@NaYF4), respectively. b, g, l, PL spectra (b), Influence of activator concentration (g), and PL decay curve (l) of Yb-PLNPs. c, h, m, PL spectra (c), Influence of activator concentration (h), and PL decay curve (m) of Pr-PLNPs. d, i, n, PL spectra (d), Influence of activator concentration (i), and PL decay curve (n) of Tb-PLNPs. e, j, o, PL spectra (e), Influence of activator concentration (j), and PL decay curve (o) of Dy-PLNPs. f, k, p, PL spectra (f), Influence of activator concentration (k), and PL decay curve (p) of Sm-PLNPs. n = 3 independent experiments. Yb-PLNPs were imaged using an InGaAs CCD camera with 5 s exposure time; Pr-PLNPs, Tb-PLNPs, Dy-PLNPs and Sm-PLNPs were imaged using a SCMOS camera with 1 s exposure time. The data are shown as the mean ± s.d.

Source data

Extended Data Fig. 6 Synthesis and characterization of multilayered and codoped Ln-PLNPs.

a, Synthesis process and corresponding TEM images of multilayered Er/Nd/Ho-PLNPs. b, Electron energy-loss spectroscopy (EELS) line scan, conducted with HAADF-STEM imaging (inset) on a multilayered Er/Nd/Ho-PLNP, showing that Gd signals in different regions of the crystal are consistent with the designed multilayered structure. c, The corresponding NIR-II PL decay curves of multilayered Er/Nd/Ho-PLNPs in Er-channel, Nd-channel, and Ho-channel, respectively. d, Synthesis process and corresponding TEM images of codoped Er/Nd/Ho-PLNPs. e, The corresponding NIR-II PL decay curves of codoped Er/Nd/Ho-PLNPs in Er-channel, Nd-channel and Ho-channel, respectively. NIR-II PL decay curves were abstracted from corresponding images with 5 s exposure time.

Source data

Extended Data Fig. 7 Influence of sample concentration and temperature on the ratio of persistent luminescence signals.

Although the PL signals of Nd-channel and Ho-channel in multilayered Nd/Ho-PLNPs (NaYF4:1%Ho@NaGdF4@NaYF4:1%Nd@NaGdF4) both decay over time, the PL ratio (INd/IHo) between the two channels is consistent, independent of sample concentration, surrounding temperature and PL signal duration. NIR-II PL decay curves were abstracted from corresponding images with 5 s exposure time.

Extended Data Fig. 8 The biocompatibility of Ln-PLNPs.

a,b, cell viabilities of 4T1 cells (a) and HEK-293 cells (b) incubated with Er-PLNPs and Nd-PLNP for 24 hours. n = 5 independent experiments. C, H&E staining of visceral organs (heart, liver, spleen, lung and kidney), obtained at 24 h post-injection of H2O (100 μL, control group), Er-PLNPs or Nd-PLNPs (0.2 mM in H2O, 100 μL) via the tail vein. These results indicated that Er-PLNPs and Nd-PLNPs have good biocompatibility and low toxicity. The data are shown as the mean ± s.d.

Source data

Extended Data Fig. 9 In vivo NIR-II persistent luminescence and NIR-II fluorescence imaging of tumours using Nd-PLNPs (NaYF4:1%Nd@NaYF4).

a–c, NIR-II PL images (a), NIR-II FL images (b) and optical photos (c) of ultrasmall CT-26 tumours in a living mouse. d, Corresponding intensity profiles of NIR-II PL images in a and NIR-II FL images in b overtime. e, Normalized intensity profiles of NIR-II PL image (t = 10 s) and NIR-II FL image (808 nm laser power: 4 mWcm−2). f, Tumour-to-normal tissue (T/N) ratios of the tumour 2 shown in a and b as a function of time (n = the number of pixels within the corresponding ROI in a and b). Scale bar: 1 cm. Imaging exposure time for PL and FL imaging is 10 s and 0.1 s, respectively. Nd-PLNPs were injected into ultra-small tumors (1.5–3.5 mm) of living mice. NIR-II PL imaging of tumour showed sharper FWHM (0.94-fold for tumour 1, 0.89-fold for tumour 2, and 0.66-fold for tumour 3) than that of NIR-II FL imaging due to reduced background noise without excitation light. Meanwhile, the tumour-to-normal tissue (T/N) ratio recorded from PL imaging reached 437.6 after injection for 10 s, which was ~ 65.3-fold higher than that of NIR-II FL (~ 6.7). Although the T/N ratios decreased with PL signal attenuation, they maintained above ~ 36 over 60 min, which was 7 times higher than the Rose criterion.

Source data

Extended Data Fig. 10 Multimodal imaging of tumours in a living mouse using NaYF4:3%Er@NaGdF4-(18F) probe.

a, HAADF-STEM image of NaYF4:3%Er@NaGdF4 nanoparticles. b, Element mapping of NaYF4:3%Er@NaGdF4 nanoparticles. c, Relaxation rate R1 (1/T1) versus various Gd3+ concentrations of NaYF4:3%Er@NaGdF4 nanoparticles (0.03, 0.06, 0.12, and 0.24 mM) at room temperature. d, PL, MR and PET imaging of the tumour on a living mouse after intratumoural injection of NaYF4:3%Er@NaGdF4-(18F) probe. Scale bar: 1 cm. This is the first investigation of combined PET, MRI and NIR-II PL signals into single nanoparticles for multimodal in vivo imaging of tumours. In comparison, conventional PL materials are mainly large crystals, which are grown at extremely high temperatures (> 1000 °C) and lack nanostructured modulation and designability, thus hampering advanced multimodal bioimaging and biosensing. Because the signals of PET and MRI are affected by 18F and Gd3+, respectively, similar performance to reported 18F-labeled NaGdF4-based probes can be obtained using our NaYF4:3%Er@NaGdF4-(18F) PLNPs. The longitudinal proton relaxation rate (R1) as a function of Gd3+ concentration in our NaYF4:3%Er@NaGdF4 led to a R1 relaxivity of 18.7 mM−1·s−1, which is lower than that of NaGdF4-based probes (28.39 mM−1·s−1)51 but is 5.4-fold higher than that of clinically used Gd-DTPA (3.45 mM−1·s−1)52.

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Pei, P., Chen, Y., Sun, C. et al. X-ray-activated persistent luminescence nanomaterials for NIR-II imaging. Nat. Nanotechnol. 16, 1011–1018 (2021). https://doi.org/10.1038/s41565-021-00922-3

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