An ultrasound-scanning in vivo light source

Nature Materials (2026)Cite this article 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 Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any timeSubscribe to this journal Receive 12 print issues and online access $259.00 per yearonly $21.58 per issueBuy this articleUSD 39.95Prices may be subject to local taxes which are calculated during checkoutThe data that support the findings of this study are available within this article and its Supplementary Information. Source data are provided with this paper.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).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 Hosang, L. et al. The lung microbiome regulates brain autoimmunity. Nature 603, 138–144 (2022).Article CAS PubMed Google Scholar Simon, H. A. in Facets of Systems Science 457–476 (Springer, 1991).Sahasrabudhe, A., Cea, C. & Anikeeva, P. Multifunctional bioelectronics for brain–body circuits. Nat. Rev. Bioeng 3, 465–484 (2025).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 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 Shahriari, D., Rosenfeld, D. & Anikeeva, P. Emerging frontier of peripheral nerve and organ interfaces. Neuron 108, 270–285 (2020).Article CAS PubMed Google Scholar 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 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 Hong, G., Antaris, A. L. & Dai, H. Near-infrared fluorophores for biomedical imaging. Nat. Biomed. Eng. 1, 0010 (2017).Article CAS Google Scholar 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 Darmani, G. et al. Non-invasive transcranial ultrasound stimulation for neuromodulation. Clin. Neurophysiol. 135, 51–73 (2022).Article CAS PubMed Google Scholar Guo, H. et al. Ultrasound produces extensive brain activation via a cochlear pathway. Neuron 98, 1020–1030.e4 (2018).Article CAS PubMed Google Scholar 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).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 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 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 Chen, S. et al. Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. Science 359, 679–684 (2018).Article CAS PubMed Google Scholar 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 Prominski, A. et al. Porosity-based heterojunctions enable leadless optoelectronic modulation of tissues. Nat. Mater. 21, 647–655 (2022).Article CAS PubMed Google Scholar Kim, Y. J. et al. Magnetoelectric nanodiscs enable wireless transgene-free neuromodulation. Nat. Nanotechnol. 20, 121–131 (2025).Article CAS PubMed Google Scholar 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 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 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 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 Bar-Zion, A. et al. Acoustically triggered mechanotherapy using genetically encoded gas vesicles. Nat. Nanotechnol. 16, 1403–1412 (2021).Article CAS PubMed Google Scholar Maresca, D. et al. Biomolecular ultrasound and sonogenetics. Annu. Rev. Chem. Biomol. Eng. 9, 229–252 (2018).Article PubMed PubMed Central Google Scholar 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 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 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 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 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 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 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 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 Stride, E. & Coussios, C. Nucleation, mapping and control of cavitation for drug delivery. Nat. Rev. Phys. 1, 495–509 (2019).Article CAS Google Scholar 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 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 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 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 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 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 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 Kubanek, J. et al. Ultrasound modulates ion channel currents. Sci. Rep. 6, 24170 (2016).Article CAS PubMed PubMed Central Google Scholar 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Menozzi, L. & Yao, J. Deep tissue photoacoustic imaging with light and sound. npj Imaging 2, 44 (2024).Article PubMed PubMed Central Google Scholar 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 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 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 Cohen, J.

Statistical Power Analysis for the Behavioral Sciences (Routledge, 2013).ShanJiang. ShanJiang1233/Jiang_2025: v1.0. Zenodo https://doi.org/10.5281/zenodo.18609351 (2026).Download referencesWe 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.Department of Materials Science and Engineering, Stanford University, Stanford, CA, USAShan Jiang, Marigold G. Malinao, Fan Yang, Xiang Wu, Su Zhao, Han Cui & Guosong HongWu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USAShan Jiang, Marigold G. Malinao, Fan Yang, Xiang Wu, Nicholas J. Rommelfanger, Su Zhao, Han Cui, Jun Ding & Guosong HongDepartment of Neuroscience, University of Virginia, Charlottesville, VA, USAShan Jiang, Silky S. Hou, Lata Chaunsali & Harald SontheimerAlfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USAYushun Zeng & Qifa ZhouDepartment of Applied Physics, Stanford University, Stanford, CA, USANicholas J. RommelfangerDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USAJun DingDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USAJun DingDepartment of Biology, Stanford University, Stanford, CA, USAXiaoke ChenSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarS.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.Correspondence to Guosong Hong.The authors declare no competing interests.Nature Materials thanks Huiliang Wang 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.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 dataa, 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 dataa, 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 dataSupplementary Video Legends 1–4, Note 1, Figs. 1–31, Table 1 and refs. 1–5.Dynamic ultrasound-mediated photostimulation of the left striatum in freely moving D1–Cre::ChR2–YFP mouse.Dynamic ultrasound-mediated photostimulation of the right striatum in freely moving D1–Cre::ChR2–YFP mouse.Dynamic ultrasound-mediated photostimulation of the left striatum in freely moving A2a–Cre::ChR2–YFP mouse.Dynamic ultrasound-mediated photostimulation of the right striatum in freely moving A2a–Cre::ChR2–YFP mouse.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.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 permissionsJiang, 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-zDownload citationReceived: 29 May 2025Accepted: 20 February 2026Published: 13 April 2026Version of record: 13 April 2026DOI: https://doi.org/10.1038/s41563-026-02556-zAnyone you share the following link with will be able to read this content:Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative