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Peer-reviewedCC BYNature Methods

A multimodal adaptive optical microscope for in vivo imaging from molecules to organisms

  • Tian-ming Fu B1,2
  • Gaoxiang Liu3,4
  • Daniel Edward Milkie1,2
  • Xiongtao Ruan3,4
  • Frederik Görlitz3,4
  • Yu Shi5
  • Valentina Ferro3,4
  • Nikita S. Divekar3,4
  • Wei Wang6,7,8
  • Harrison M. York9
  • Velat Kilic1,2
  • Matthew Mueller3,1,4,2
38 more authors
  • Yajie Liang10
  • Timothy A. Daugird11
  • María José Gacha Garay12
  • Kathryn A. Larkin12
  • Rebecca C. Adikes12
  • N Harrison3,4
  • Cyna R. Shirazinejad13,3,4
  • Shara C. Williams3,4
  • Jamison L. Nourse14
  • Shu‐Hsien Sheu1,2
  • Liang Gao1,2
  • Tongchao Li15
  • Chandrani Mondal16
  • Kemal Achour3,4
  • Wilmene Hercule3,4
  • Daniel R. Stabley17
  • Kevin Emmerich18,19
  • Peng Dong1,2
  • David G. Drubin3,4
  • Zhe J. Liu1,2
  • David E. Clapham1,2
  • Jeff S. Mumm18,19
  • Minoru Koyama20
  • Alison N. Killilea3,4
  • Jose Javier Bravo‐Cordero16
  • Christopher Dirk Keene21
  • Liqun Luo15
  • Tomas L. Kirchhausen22,23,24
  • Medha M. Pathak25,14
  • Senthil Arumugam26,9
  • James K. Nuñez3,4
  • Ruixuan Gao27,6,7
  • David Q. Matus12
  • Benjamin L. Martin12
  • Ian A. Swinburne3,4
  • Eric Betzig3,28,1,4,2
  • Wesley R. Legant11,5
  • Srigokul Upadhyayula29,3,30,4
30 affiliations
  1. 1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 20147, USA
  2. 2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 2047, USA
  3. 3Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA
  4. 4Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 9470, USA
  5. 5Lampe Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  6. 6Department of Chemistry, University of Illinois Chicago; Chicago, IL 60607, USA
  7. 7Chicago, IL 60607, USA
  8. 8Department of Chemistry, University of Illinois Chicago
  9. 9Monash Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton/Melbourne, VIC, 3800, Australia
  10. 10Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
  11. 11Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  12. 12Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215, USA
  13. 13Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA, USA
  14. 14Department of Physiology and Biophysics, Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine 92697, USA
  15. 15Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States
  16. 16Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  17. 17Neuroimaging Laboratory, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
  18. 18McKusick-Nathans Institute and the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
  19. 19Wilmer Eye Institute and the Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
  20. 20University of Toronto, Department of Cell and Systems Biology, Scarborough, Ontario, Canada
  21. 21University of Washington BioRepository and Integrated Neuropathology (BRaIN) lab, Harborview Medical Center, Seattle, WA, USA
  22. 22Department of Cell Biology, Harvard Medical School, Boston, MA 02115
  23. 23Department of Pediatrics, Harvard Medical School, Boston, MA 02115
  24. 24Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115
  25. 25Department of Biomedical Engineering, and Center for Complex Systems Biology, University of California, Irvine, CA 92697 University of California, Irvine, Irvine 92697, USA
  26. 26European Molecular Laboratory Australia, Monash University, Clayton/ Melbourne, VIC 3800, Australia
  27. 27Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA
  28. 28Department of Physics, Howard Hughes Medical Institute, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA
  29. 29Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
  30. 30Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Open at sourceDOICite

Abstract

Understanding biological systems requires observing features and processes across vast spatial and temporal scales, spanning nanometers to centimeters and milliseconds to days, often using multiple imaging modalities within complex native microenvironments. Yet, achieving this comprehensive view is challenging because microscopes optimized for specific tasks typically lack versatility due to inherent optical and sample handling trade-offs, and frequently suffer performance degradation from sample-induced optical aberrations in multicellular contexts. Here, we present MOSAIC, a reconfigurable microscope that integrates multiple advanced imaging techniques including light-sheet, label-free, super-resolution, and multi-photon, all equipped with adaptive optics. MOSAIC enables non-invasive imaging of subcellular dynamics in both cultured cells and live multicellular organisms, nanoscale mapping of molecular architectures across millimeter-scale expanded tissues, and structural/functional neural imaging within live mice. MOSAIC facilitates correlative studies across biological scales within the same specimen, providing an integrated platform for broad biological investigation.

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Cite

BibTeXRIS
BibTeX
@article{fu2026multimodal,
  title = {{A multimodal adaptive optical microscope for in vivo imaging from molecules to organisms}},
  author = {Tian-ming Fu B and Gaoxiang Liu and Daniel Edward Milkie and Xiongtao Ruan and Frederik Görlitz and Yu Shi and Valentina Ferro and Nikita S. Divekar and Wei Wang and Harrison M. York and Velat Kilic and Matthew Mueller and Yajie Liang and Timothy A. Daugird and María José Gacha Garay and Kathryn A. Larkin and Rebecca C. Adikes and N Harrison and Cyna R. Shirazinejad and Shara C. Williams and Jamison L. Nourse and Shu‐Hsien Sheu and Liang Gao and Tongchao Li and Chandrani Mondal and Kemal Achour and Wilmene Hercule and Daniel R. Stabley and Kevin Emmerich and Peng Dong and David G. Drubin and Zhe J. Liu and David E. Clapham and Jeff S. Mumm and Minoru Koyama and Alison N. Killilea and Jose Javier Bravo‐Cordero and Christopher Dirk Keene and Liqun Luo and Tomas L. Kirchhausen and Medha M. Pathak and Senthil Arumugam and James K. Nuñez and Ruixuan Gao and David Q. Matus and Benjamin L. Martin and Ian A. Swinburne and Eric Betzig and Wesley R. Legant and Srigokul Upadhyayula},
  journal = {Nature Methods},
  year = {2026},
  month = may,
  doi = {10.1038/s41592-026-03066-1},
  url = {https://doi.org/10.1038/s41592-026-03066-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A multimodal adaptive optical microscope for in vivo imaging from molecules to organisms
AU  - Tian-ming Fu B
AU  - Gaoxiang Liu
AU  - Daniel Edward Milkie
AU  - Xiongtao Ruan
AU  - Frederik Görlitz
AU  - Yu Shi
AU  - Valentina Ferro
AU  - Nikita S. Divekar
AU  - Wei Wang
AU  - Harrison M. York
AU  - Velat Kilic
AU  - Matthew Mueller
AU  - Yajie Liang
AU  - Timothy A. Daugird
AU  - María José Gacha Garay
AU  - Kathryn A. Larkin
AU  - Rebecca C. Adikes
AU  - N Harrison
AU  - Cyna R. Shirazinejad
AU  - Shara C. Williams
AU  - Jamison L. Nourse
AU  - Shu‐Hsien Sheu
AU  - Liang Gao
AU  - Tongchao Li
AU  - Chandrani Mondal
AU  - Kemal Achour
AU  - Wilmene Hercule
AU  - Daniel R. Stabley
AU  - Kevin Emmerich
AU  - Peng Dong
AU  - David G. Drubin
AU  - Zhe J. Liu
AU  - David E. Clapham
AU  - Jeff S. Mumm
AU  - Minoru Koyama
AU  - Alison N. Killilea
AU  - Jose Javier Bravo‐Cordero
AU  - Christopher Dirk Keene
AU  - Liqun Luo
AU  - Tomas L. Kirchhausen
AU  - Medha M. Pathak
AU  - Senthil Arumugam
AU  - James K. Nuñez
AU  - Ruixuan Gao
AU  - David Q. Matus
AU  - Benjamin L. Martin
AU  - Ian A. Swinburne
AU  - Eric Betzig
AU  - Wesley R. Legant
AU  - Srigokul Upadhyayula
PY  - 2026
DA  - 2026/05/22
JO  - Nature Methods
DO  - 10.1038/s41592-026-03066-1
UR  - https://doi.org/10.1038/s41592-026-03066-1
AB  - Understanding biological systems requires observing features and processes across vast spatial and temporal scales, spanning nanometers to centimeters and milliseconds to days, often using multiple imaging modalities within complex native microenvironments. Yet, achieving this comprehensive view is challenging because microscopes optimized for specific tasks typically lack versatility due to inherent optical and sample handling trade-offs, and frequently suffer performance degradation from sample-induced optical aberrations in multicellular contexts. Here, we present MOSAIC, a reconfigurable microscope that integrates multiple advanced imaging techniques including light-sheet, label-free, super-resolution, and multi-photon, all equipped with adaptive optics. MOSAIC enables non-invasive imaging of subcellular dynamics in both cultured cells and live multicellular organisms, nanoscale mapping of molecular architectures across millimeter-scale expanded tissues, and structural/functional neural imaging within live mice. MOSAIC facilitates correlative studies across biological scales within the same specimen, providing an integrated platform for broad biological investigation.
SN  - 1548-7091
SN  - 1548-7105
ER  -