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Peer-reviewedCC BY 4.0Nature Methods

Near-infrared photochromic miniprotein enables photoacoustic molecular imaging of acute inflammation and intracellular antigens

  • Olena S. Oliinyk1
  • Yirui Xu2
  • Jinhuan Luo2
  • Kateryna O. Tokarchuk1
  • Kyrylo Yu. Manoilov3
  • Josie van de Klashorst2
  • Matthew P. Eyring2
  • Mu-en Wang4
  • Ming Chen4
  • Pengfei Song2
  • John W. Hickey2
  • Junjie Yao2
1 more authors
  • Vladislav V. Verkhusha1,3
4 affiliations
  1. 1Department of Anatomy, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  2. 2Department of Biomedical Engineering, School of Engineering, Duke University, Durham, NC USA
  3. 3Department of Genetics and Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY USA
  4. 4Department of Pathology, School of Medicine, Duke University, Durham, NC USA
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Abstract

Using near-infrared photoswitchable photochromic genetically encoded probes, differential photoacoustic tomography (PAT) enables deep-tissue imaging with high resolution and sensitivity; however, current bacteriophytochrome-based probes are bulky multidomain proteins exceeding 55 kDa, which constrains their use for designing PAT molecular reporters. Here we engineer rsmiRFPnano, a compact cyanobacteriochrome-derived photoswitchable PAT probe. With a molecular weight below 19 kDa, rsmiRFPnano efficiently incorporates biliverdin, exhibits high extinction coefficients in both photochromic states and demonstrates robust performance in live cells. We established rsmiRFPnano-based reporters for NF-κB and AP-1 pathways, which display low basal activity and strong activation-dependent responses. These reporters effectively visualized acute inflammation using noninvasive PAT in vivo, further validated through cellular-level spatial omics mapping. We then created photoswitchable nanobody probes, rsNIR-Fbs, stabilized upon antigen binding and rapidly degraded otherwise, enabling selective photoacoustic immuno-imaging of intracellular antigens in vivo. Together, these results establish rsmiRFPnano as an ultracompact and versatile platform for molecular PAT.

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Cite

BibTeXRIS
BibTeX
@article{oliinyk2026nearinfrared,
  title = {{Near-infrared photochromic miniprotein enables photoacoustic molecular imaging of acute inflammation and intracellular antigens}},
  author = {Olena S. Oliinyk and Yirui Xu and Jinhuan Luo and Kateryna O. Tokarchuk and Kyrylo Yu. Manoilov and Josie van de Klashorst and Matthew P. Eyring and Mu-en Wang and Ming Chen and Pengfei Song and John W. Hickey and Junjie Yao and Vladislav V. Verkhusha},
  journal = {Nature Methods},
  year = {2026},
  month = oct,
  doi = {10.1038/s41592-026-03255-y},
  url = {https://doi.org/10.1038/s41592-026-03255-y},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Near-infrared photochromic miniprotein enables photoacoustic molecular imaging of acute inflammation and intracellular antigens
AU  - Olena S. Oliinyk
AU  - Yirui Xu
AU  - Jinhuan Luo
AU  - Kateryna O. Tokarchuk
AU  - Kyrylo Yu. Manoilov
AU  - Josie van de Klashorst
AU  - Matthew P. Eyring
AU  - Mu-en Wang
AU  - Ming Chen
AU  - Pengfei Song
AU  - John W. Hickey
AU  - Junjie Yao
AU  - Vladislav V. Verkhusha
PY  - 2026
DA  - 2026/10/13
JO  - Nature Methods
DO  - 10.1038/s41592-026-03255-y
UR  - https://doi.org/10.1038/s41592-026-03255-y
AB  - Using near-infrared photoswitchable photochromic genetically encoded probes, differential photoacoustic tomography (PAT) enables deep-tissue imaging with high resolution and sensitivity; however, current bacteriophytochrome-based probes are bulky multidomain proteins exceeding 55 kDa, which constrains their use for designing PAT molecular reporters. Here we engineer rsmiRFPnano, a compact cyanobacteriochrome-derived photoswitchable PAT probe. With a molecular weight below 19 kDa, rsmiRFPnano efficiently incorporates biliverdin, exhibits high extinction coefficients in both photochromic states and demonstrates robust performance in live cells. We established rsmiRFPnano-based reporters for NF-κB and AP-1 pathways, which display low basal activity and strong activation-dependent responses. These reporters effectively visualized acute inflammation using noninvasive PAT in vivo, further validated through cellular-level spatial omics mapping. We then created photoswitchable nanobody probes, rsNIR-Fbs, stabilized upon antigen binding and rapidly degraded otherwise, enabling selective photoacoustic immuno-imaging of intracellular antigens in vivo. Together, these results establish rsmiRFPnano as an ultracompact and versatile platform for molecular PAT.
SN  - 1548-7091
SN  - 1548-7105
ER  -