Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An ultrasound-scanning in vivo light source

Abstract

Biological systems operate across distributed regions with fast, localized dynamics, yet existing biointerfaces fall short of providing both high spatiotemporal precision and the ability to dynamically target any region without disturbing surrounding tissue. Here we present an in vivo deep-tissue light source based on focused ultrasound scanning of mechanoluminescent nanotransducers circulating through the vasculature. We demonstrate the programmability of this approach in tissue-mimicking phantoms and the endogenous circulatory system of animals, where tunable spatial resolution and dynamic light patterning are achieved. We validate the functionality of the ultrasound-scanning light source in opsin-expressing neurons through electrophysiological recordings and immunostaining in both the brain and the spinal cord. We showcase dynamic three-dimensional brain targeting and temporally resolved behavioural control in freely moving animals via the ultrasound-scanning in vivo light source. This non-invasive deep-tissue light source offers a versatile strategy for body-wide optical interfacing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Optical scanning of biological systems via an ultrasound-mediated light source.
Fig. 2: An ultrasound-scanning light source based on MLNTs.
Fig. 3: An ultrasound-scanning light source in circulatory systems.
Fig. 4: Validating the efficacy of the ultrasound-scanning in vivo light source with electrophysiological recording.
Fig. 5: Validating the efficacy of the ultrasound-scanning light source that dynamically targets multiple brain regions.
Fig. 6: Ultrasound-scanning light source enables dynamic targeting of distinct deep-brain regions in free-moving mice.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available within this article and its Supplementary Information. Source data are provided with this paper.

Code availability

The custom MATLAB code used in this study for spike sorting is available at https://github.com/ShanJiang1233/Jiang_2025 and is archived at Zenodo at https://doi.org/10.5281/zenodo.18609351 (ref. 65).

References

  1. Schaffer, L. V. & Ideker, T. Mapping the multiscale structure of biological systems. Cell Syst. 12, 622–635 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hosang, L. et al. The lung microbiome regulates brain autoimmunity. Nature 603, 138–144 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Simon, H. A. in Facets of Systems Science 457–476 (Springer, 1991).

  4. Sahasrabudhe, A., Cea, C. & Anikeeva, P. Multifunctional bioelectronics for brain–body circuits. Nat. Rev. Bioeng 3, 465–484 (2025).

  5. Hong, G. & Lieber, C. M. Novel electrode technologies for neural recordings. Nat. Rev. Neurosci. 20, 330–345 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Won, S. M., Cai, L., Gutruf, P. & Rogers, J. A. Wireless and battery-free technologies for neuroengineering. Nat. Biomed. Eng. 7, 405–423 (2023).

    Article  PubMed  Google Scholar 

  7. Shahriari, D., Rosenfeld, D. & Anikeeva, P. Emerging frontier of peripheral nerve and organ interfaces. Neuron 108, 270–285 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Zhu, X., Menozzi, L., Cho, S.-W. & Yao, J. High speed innovations in photoacoustic microscopy. npj Imaging 2, 46 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hu, Z. et al. Airy-beam holographic sonogenetics for advancing neuromodulation precision and flexibility. Proc. Natl Acad. Sci. USA 121, e2402200121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hong, G., Antaris, A. L. & Dai, H. Near-infrared fluorophores for biomedical imaging. Nat. Biomed. Eng. 1, 0010 (2017).

    Article  CAS  Google Scholar 

  11. Yun, S. H. & Kwok, S. J. J. Light in diagnosis, therapy and surgery. Nat. Biomed. Eng. 1, 0008 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Darmani, G. et al. Non-invasive transcranial ultrasound stimulation for neuromodulation. Clin. Neurophysiol. 135, 51–73 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Guo, H. et al. Ultrasound produces extensive brain activation via a cochlear pathway. Neuron 98, 1020–1030.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Szablowski, J. O., Lee-Gosselin, A., Lue, B., Malounda, D. & Shapiro, M. G. Acoustically targeted chemogenetics for the non-invasive control of neural circuits. Nat. Biomed. Eng 2, 475–484 (2018).

  15. Ouyang, W. et al. A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals. Nat. Biomed. Eng. 7, 1252–1269 (2023).

    Article  PubMed  Google Scholar 

  16. Wang, W. et al. Ultrasound-induced cascade amplification in a mechanoluminescent nanotransducer for enhanced sono-optogenetic deep brain stimulation. ACS Nano 17, 24936–24946 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang, Y. et al. Rational design of silicon structures for optically controlled multiscale biointerfaces. Nat. Biomed. Eng. 2, 508–521 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, S. et al. Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. Science 359, 679–684 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Wu, X. et al. Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nat. Biomed. Eng. 6, 754–770 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prominski, A. et al. Porosity-based heterojunctions enable leadless optoelectronic modulation of tissues. Nat. Mater. 21, 647–655 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Kim, Y. J. et al. Magnetoelectric nanodiscs enable wireless transgene-free neuromodulation. Nat. Nanotechnol. 20, 121–131 (2025).

    Article  CAS  PubMed  Google Scholar 

  22. Chen, R., Romero, G., Christiansen, M. G., Mohr, A. & Anikeeva, P. Wireless magnetothermal deep brain stimulation. Science 347, 1477–1480 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Sebesta, C. et al. Subsecond multichannel magnetic control of select neural circuits in freely moving flies. Nat. Mater. 21, 951–958 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang, Y. et al. Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound. Nat. Metab. 5, 789–803 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuang, X. et al. Self-enhancing sono-inks enable deep-penetration acoustic volumetric printing. Science 382, 1148–1155 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bar-Zion, A. et al. Acoustically triggered mechanotherapy using genetically encoded gas vesicles. Nat. Nanotechnol. 16, 1403–1412 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Maresca, D. et al. Biomolecular ultrasound and sonogenetics. Annu. Rev. Chem. Biomol. Eng. 9, 229–252 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hurt, R. C. et al. Genomically mined acoustic reporter genes for real-time in vivo monitoring of tumors and tumor-homing bacteria. Nat. Biotechnol. 41, 919–931 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heiles, B. et al. Nonlinear sound-sheet microscopy: imaging opaque organs at the capillary and cellular scale. Science 388, eads1325 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cadoni, S. et al. Ectopic expression of a mechanosensitive channel confers spatiotemporal resolution to ultrasound stimulations of neurons for visual restoration. Nat. Nanotechnol. 18, 667–676 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang, F. et al. Palette of rechargeable mechanoluminescent fluids produced by a biomineral-inspired suppressed dissolution approach. J. Am. Chem. Soc. 144, 18406–18418 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang, W. et al. H-bonded organic frameworks as ultrasound-programmable delivery platform. Nature 638, 401–410 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, T. et al. Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound. Nat. Biomed. Eng. 7, 149–163 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Banishev, A. A. & Banishev, A. F. B. Photoluminescence features and mechanoluminescence mechanism inherent in composite materials based on a photopolymerizing resin and finely dispersed powders of SrAl2O4:(Eu2+,Dy3+) and Sr4Al14O25:(Eu2+,Dy3+,B) luminophores. Inorg. Mater. Appl. Res. 9, 484–489 (2018).

    Article  Google Scholar 

  35. Kalita, J. M. & Chithambo, M. L. Probing the electron trap-depth distribution in Sr4Al14O25:Eu2+,Dy3+. J. Lumin. 265, 120245 (2024).

    Article  CAS  Google Scholar 

  36. Stride, E. & Coussios, C. Nucleation, mapping and control of cavitation for drug delivery. Nat. Rev. Phys. 1, 495–509 (2019).

    Article  CAS  Google Scholar 

  37. Klapoetke, N. C. et al. Independent optical excitation of distinct neural populations. Nat. Methods 11, 338–346 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou, X. X., Fan, L. Z., Li, P., Shen, K. & Lin, M. Z. Optical control of cell signaling by single-chain photoswitchable kinases. Science 355, 836–842 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Xiong, B. et al. Precise cerebral vascular atlas in stereotaxic coordinates of whole mouse brain. Front. Neuroanat. 11, 128 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Jiang, S. et al. Spatially expandable fiber-based probes as a multifunctional deep brain interface. Nat. Commun. 11, 6115 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yoo, S., Mittelstein, D. R., Hurt, R. C., Lacroix, J. & Shapiro, M. G. Focused ultrasound excites cortical neurons via mechanosensitive calcium accumulation and ion channel amplification. Nat. Commun. 13, 493 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Owen, S. F., Liu, M. H. & Kreitzer, A. C. Thermal constraints on in vivo optogenetic manipulations. Nat. Neurosci. 22, 1061–1065 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sato, T., Shapiro, M. G. & Tsao, D. Y. Ultrasonic neuromodulation causes widespread cortical activation via an indirect auditory mechanism. Neuron 98, 1031–1041.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kubanek, J. et al. Ultrasound modulates ion channel currents. Sci. Rep. 6, 24170 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sheng, M. & Greenberg, M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4, 477–485 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Stujenske, J. M., Spellman, T. & Gordon, J. A. Modeling the spatiotemporal dynamics of light and heat propagation for in vivo optogenetics. Cell Rep. 12, 525–534 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Qian, H., Sheetz, M. P. & Elson, E. L. Single particle tracking. Analysis of diffusion and flow in two-dimensional systems. Biophys. J. 60, 910–921 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kravitz, A. V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Grimm, C. et al. Optogenetic activation of striatal D1R and D2R cells differentially engages downstream connected areas beyond the basal ganglia. Cell Rep. 37, 110161 (2021).

    Article  CAS  PubMed  Google Scholar 

  50. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Madisen, L. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793–802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lu, J. et al. Alcohol intake enhances glutamatergic transmission from D2 receptor-expressing afferents onto D1 receptor-expressing medium spiny neurons in the dorsomedial striatum. Neuropsychopharmacology 44, 1123–1131 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Varin, C., Cornil, A., Houtteman, D., Bonnavion, P. & de Kerchove d’Exaerde, A. The respective activation and silencing of striatal direct and indirect pathway neurons support behavior encoding. Nat. Commun. 14, 4982 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou, X. X. et al. A single-chain photoswitchable CRISPR-Cas9 architecture for light-inducible gene editing and transcription. ACS Chem. Biol. 13, 443–448 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Pulgarin, D. V. et al. Light-induced expression of gRNA allows for optogenetic gene editing of T lymphocytes in vivo. Nucleic Acids Res. 53, gkaf213 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li, X., Lovell, J. F., Yoon, J. & Chen, X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 17, 657–674 (2020).

    Article  PubMed  Google Scholar 

  58. Obaid, G. et al. Engineering photodynamics for treatment, priming and imaging. Nat. Rev. Bioeng 2, 752–769 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu, C. et al. Nanoparticles with ultrasound-induced afterglow luminescence for tumour-specific theranostics. Nat. Biomed. Eng. 7, 298–312 (2023).

    Article  CAS  PubMed  Google Scholar 

  60. Menozzi, L. & Yao, J. Deep tissue photoacoustic imaging with light and sound. npj Imaging 2, 44 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Linsley, C. S. & Wu, B. M. Recent advances in light-responsive on-demand drug-delivery systems. Ther. Deliv. 8, 89–107 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tsai, M.-F. et al. Near-infrared light-triggered drug release from ultraviolet- and redox-responsive polymersome encapsulated with core–shell upconversion nanoparticles for cancer therapy. ACS Appl. Bio Mater. 4, 3264–3275 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Jiang, S., Wu, X., Yang, F., Rommelfanger, N. J. & Hong, G. Activation of mechanoluminescent nanotransducers by focused ultrasound enables light delivery to deep-seated tissue in vivo. Nat. Protoc. 18, 3787–3820 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cohen, J. Statistical Power Analysis for the Behavioral Sciences (Routledge, 2013).

  65. ShanJiang. ShanJiang1233/Jiang_2025: v1.0. Zenodo https://doi.org/10.5281/zenodo.18609351 (2026).

Download references

Acknowledgements

We thank A. Deniz Guler for donation of D1–cre mice and the University of Virginia School of Medicine Research Histology Core Facility for help with the preparation of histologic specimens. Part of the confocal microscopy imaging was performed at the Stanford Wu Tsai Neuroscience Microscopy Service. G.H. acknowledges three awards by NIH (5R00AG056636-04, 1R34NS127103-01 and R01NS126076-01), a National Science Foundation (NSF) CAREER Award (2045120), an NSF EAGER Award (2217582), a Rita Allen Foundation Scholars Award, a Beckman Technology Development Grant, a grant from the Focused Ultrasound Foundation, a gift from the Spinal Muscular Atrophy Foundation, a gift from the Pinetops Foundation, two seed grants from the Wu Tsai Neurosciences Institute, two seed grants from the Bio-X Initiative of Stanford University and a Synthetic Neurobiology Grant of Stanford University. H.S. acknowledges four awards by NIH (R01AG072430, R56 AG077720, R01AG085359 and R01NS123069). S.J. acknowledges support by the BRAIN Postdoctoral Fellowship from the University of Virginia. M.G.M. and N.J.R. acknowledge support by Bio-X Graduate Student Fellowships. M.G.M. and N.J.R. acknowledge support by the NSF Graduate Research Fellowships Program (award 1656518). X.W. acknowledges support by a Stanford Graduate Fellowship. X.C. acknowledges four awards by NIH (R01NS129834, R01DA059602, R01MH116904 and R01DA045664). Some illustrations were created with BioRender.com.

Author information

Authors and Affiliations

Authors

Contributions

S.J., X.C., J.D., H.S. and G.H. conceived and designed the project; S.J., M.G.M. and F.Y. synthesized MLNTs; F.Y. and H.C. performed the structure and morphology characterizations; S.J., F.Y. and N.J.R. performed the optical characterizations; S.J., M.G.M. and N.J.R. performed the pressure mapping; S.J. and X.W. performed imaging of the mechanoluminescence emission from the mouse; S.J. and M.G.M performed in vivo fibre photometry; S.J. performed the electrophysiological recording; S.J. performed the immunostaining and confocal microscopy imaging; S.J. and S.Z. performed the evaluation of recharging efficiency; Y.Z. and Q.Z. fabricated and validated the wearable transducer; S.J. designed the head-mounted system; S.J. and S.S.H. performed the behaviour assays; S.J., M.G.M., S.S.H. and L.C. performed the biocompatibility studies. S.J., F.Y., L.C., H.S. and G.H. analysed the data. All authors contributed to the writing of the paper.

Corresponding author

Correspondence to Guosong Hong.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Materials thanks Huiliang Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Extended data

Extended Data Fig. 1 Pressure mapping of the FUS transducers operating at different frequencies.

a-d, Acoustic pressure fields in both the lateral (x–y plane at z0 = 0, i) and axial (y–z plane, at x0 = 0, ii) planes for a 0.65-MHz transducer (a), 1.5-MHz transducer (b), 3.3-MHz transducer (c), and 5.7-MHz transducer (d). In each panel, subpanels iii and iv display the corresponding spatial pressure profiles across the dashed lines in i and ii, respectively. FWHM was used to quantify the lateral resolution, while the depth of focus (DOF), defined as the −6 dB pressure width, was used to quantify the axial resolution.

Source data

Extended Data Fig. 2 Validating the efficacy of the ultrasound-scanning in vivo light source with c-Fos immunostaining.

a, Schematic illustration of the FUS-mediated light source in the M1 region. b, Representative immunostaining images of ChR2-YFP and c-Fos in the M1 region under different experimental conditions. c, Statistical analysis of the c-Fos cell density in the M1 region across different experimental groups. d, Schematic illustration of the FUS-mediated light source in the vDG. e, Representative immunostaining images of ChR2-YFP and c-Fos in the vDG under different experimental conditions. f, Statistical analysis of the c-Fos cell density in the vDG across different experimental groups. Scale bars represent 40 µm in b and 80 µm in e. All data are presented as mean ± s.d. with data points shown for n = 3 mice in each group. Statistical significance and P values are determined by ordinary one-way ANOVA: **P < 0.01, ****P < 0.0001.

Source data

Extended Data Fig. 3 Biocompatibility assessment of the ultrasound-scanning light source.

a, e, Representative immunostaining images of the M1 region 1 week (a) and 4 weeks (e) post-procedure under different experimental conditions. b, f, Statistical analysis of neuronal density 1 week (b) and 4 weeks (f) post-procedure. c, g, Statistical analysis of GFAP area 1 week (c) and 4 weeks (g) post-procedure. d, h, Statistical analysis of Iba1 area 1 week (d) and 4 weeks (h) post-procedure. All scale bars represent 50 µm. All data are presented as mean ± s.d. with data points shown for each animal from n = 4 mice in each group. Statistical significance and P values are determined by ordinary one-way ANOVA: P ≥ 0.05 (n.s.).

Source data

Supplementary information

Supplementary Information (download PDF )

Supplementary Video Legends 1–4, Note 1, Figs. 1–31, Table 1 and refs. 1–5.

Reporting Summary (download PDF )

Supplementary Video 1 (download AVI )

Dynamic ultrasound-mediated photostimulation of the left striatum in freely moving D1–Cre::ChR2–YFP mouse.

Supplementary Video2 (download AVI )

Dynamic ultrasound-mediated photostimulation of the right striatum in freely moving D1–Cre::ChR2–YFP mouse.

Supplementary Video3 (download AVI )

Dynamic ultrasound-mediated photostimulation of the left striatum in freely moving A2a–Cre::ChR2–YFP mouse.

Supplementary Video4 (download AVI )

Dynamic ultrasound-mediated photostimulation of the right striatum in freely moving A2a–Cre::ChR2–YFP mouse.

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, S., Malinao, M.G., Yang, F. et al. An ultrasound-scanning in vivo light source. Nat. Mater. (2026). https://doi.org/10.1038/s41563-026-02556-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41563-026-02556-z

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing