Whispering-gallery-mode resonators for detection and classification of free-flowing nanoparticles and cells through photoacoustic signatures

Jie Liao; Maxwell Adolphson; Hangyue Li; Dipayon Kumar Sikder; Chenyang Lu; Lan Yang

doi:10.1038/s41377-025-01978-9

Your Location：

Home >

Browse articles >

Whispering-gallery-mode resonators for detection and classification of free-flowing nanoparticles and cells through photoacoustic signatures

Original Articles

- Whispering-gallery-mode resonators for detection and classification of free-flowing nanoparticles and cells through photoacoustic signatures
- Light: Science & Applications Vol. 14, Issue 12, Pages: 4192-4203(2025)
- Affiliations：
  
  1.Department of Electrical and Systems Engineering, Washington University, St. Louis, MO 63130, USA
  2.Department of Computer Science and Engineering, Washington University, St. Louis, MO 63130, USA
  3.AI for Health Institute, Washington University, St. Louis, MO 63130, USA
- Author bio：
  
  Lan Yang (yang@seas.wustl.edu)
- Funds：
- DOI：10.1038/s41377-025-01978-9
  CLC：
- Received：16 October 2024，
  
  Revised：2025-06-08，
  
  Accepted：22 July 2025，
  
  Published Online：11 December 2025，
  
  Published：31 December 2025
- Accepted：
Scan QR Code
Liao, J. et al. Whispering-gallery-mode resonators for detection and classification of free-flowing nanoparticles and cells through photoacoustic signatures. Light: Science & Applications, 14, 4192-4203 (2025).
DOI：

Liao, J. et al. Whispering-gallery-mode resonators for detection and classification of free-flowing nanoparticles and cells through photoacoustic signatures. Light: Science & Applications, 14, 4192-4203 (2025). DOI： 10.1038/s41377-025-01978-9.

摘要

Abstract

Micro and nanoscale particles have played crucial roles across diverse fields

from biomedical imaging and environmental processes to early disease diagnosis

influencing numerous scientific research and industrial applications. Their unique characteristics demand accurate detection

characterization

and identification. However

conventional spectroscopy and microscopy commonly used to characterize and identify tiny objects often involve bulky equipment and intricate

time-consuming sample preparation. Over the past two decades

optical micro-sensors have emerged as a promising sensor technology with their high sensitivity and compact configuration. However

their broad applicability is constrained by the requirement of surface binding for selective sensing and the difficulty in differentiating between various sensing targets

which limits their application in detecting targets in their native state or in complex biological samples. Developing label-free and immobilization-free sensing techniques that can directly detect target particles in complex solutions is crucial for overcoming the inherent limitations of current biosensors. In this study

we design and demonstrate an optofluidic

high throughput

ultra-sensitive optical microresonator sensor that can capture subtle acoustic signals

generated by tiny particles from the absorption of pulsed light energy

providing photoacoustic spectroscopy information for real-time

label-free detection and interrogation of particles and cells in their native solution environments across an extended sensing volume. Leveraging unique optical absorption of the targets

our technique can selectively detect and classify particles flowing through the sensor systems without the need for surface binding

even in a complex sample matrix

such as whole blood samples. We showcase the measurement of gold nanoparticles with diverse geometries and different species of red blood cells in the presence of other cellular elements and a wide variety of proteins. These particles are effectively identified and classified based on their photoacoustic fingerprint that captures particle shape

composition

molecule properties

and morphology features. This work opens up new avenues to achieve rapid

reliable

and high-throughput particle and cell identification in clinical and industrial applications

offering a valuable tool for understanding complex biological and environmental systems.

关键词

Keywords

references

Cho, E. J. et al. Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol. Pharm. 10 , 2093–2110 (2013)..

Baek, M. J. et al. Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Nat. Nanotechnol. 18 , 945–956 (2023)..

Riley, R. S. & Day, E. S. Gold nanoparticle-mediated photothermal therapy: applications and opportunities for multimodal cancer treatment. WIREs Nanomed. Nanobiotechnol. 9 , e1449 (2017)..

Arami, H. et al. Remotely controlled near-infrared-triggered photothermal treatment of brain tumours in freely behaving mice using gold nanostars. Nat. Nanotechnol. 17 , 1015–1022 (2022)..

Herran, M. et al. Plasmonic bimetallic two-dimensional supercrystals for H 2 generation. Nat. Catal. 6 , 1205–1214 (2023)..

Wang, F. et al. Tuning upconversion through energy migration in core–shell nanoparticles. Nat. Mater. 10 , 968–973 (2011)..

Shi, Y. Z. et al. Sculpting nanoparticle dynamics for single-bacteria-level screening and direct binding-efficiency measurement. Nat. Commun. 9 , 815 (2018)..

Stiles, P. L. et al. Surface-enhanced Raman spectroscopy. Annu. Rev. Anal. Chem. 1 , 601–626 (2008)..

Mao, W. B. et al. A whispering-gallery scanning microprobe for Raman spectroscopy and imaging. Light Sci. Appl. 12 , 247 (2023)..

Xu, Y. J. et al. Artificial intelligence: a powerful paradigm for scientific research. Innovation 2 , 100179 (2021)..

Ho, C. S. et al. Rapid identification of pathogenic bacteria using Raman spectroscopy and deep learning. Nat. Commun. 10 , 4927 (2019)..

Strohm, E. M. et al. Modeling photoacoustic spectral features of micron-sized particles. Phys. Med. Biol. 59 , 5795–5810 (2014)..

Tam, A. C. Applications of photoacoustic sensing techniques. Rev. Mod. Phys. 58 , 381–431 (1986)..

Xu, M. H. & Wang, L. V. Photoacoustic imaging in biomedicine. Rev. Sci. Instrum. 77 , 041101 (2006)..

Yao, J. J. et al. High-speed label-free functional photoacoustic microscopy of mouse brain in action. Nat. Methods 12 , 407–410 (2015)..

Zharov, V. P. Ultrasharp nonlinear photothermal and photoacoustic resonances and holes beyond the spectral limit. Nat. Photonics 5 , 110–116 (2011)..

Li, C. H. & Wang, L. V. Photoacoustic tomography and sensing in biomedicine. Phys. Med. Biol. 54 , R59–R97 (2009)..

Loyez, M. et al. From whispering gallery mode resonators to biochemical sensors. ACS Sens. 8 , 2440–2470 (2023)..

Yu, D. S. et al. Whispering-gallery-mode sensors for biological and physical sensing. Nat. Rev. Methods Prim. 1 , 83 (2021)..

Altug, H. et al. Advances and applications of nanophotonic biosensors. Nat. Nanotechnol. 17 , 5–16 (2022)..

Heylman, K. D. et al. Optical microresonators for sensing and transduction: a materials perspective. Adv. Mater. 29 , 1700037 (2017)..

Vollmer, F. et al. Protein detection by optical shift of a resonant microcavity. Appl. Phys. Lett. 80 , 4057–4059 (2002)..

Baaske, M. D. & Vollmer, F. Optical observation of single atomic ions interacting with plasmonic nanorods in aqueous solution. Nat. Photonics 10 , 733–739 (2016)..

Chen, Y. C., Chen, Q. S. & Fan, X. D. Lasing in blood. Optica 3 , 809–815 (2016)..

Martino, N. et al. Wavelength-encoded laser particles for massively multiplexed cell tagging. Nat. Photonics 13 , 720–727 (2019)..

Schubert, M. et al. Monitoring contractility in cardiac tissue with cellular resolution using biointegrated microlasers. Nat. Photonics 14 , 452–458 (2020)..

Heylman, K. D. et al. Optical microresonators as single-particle absorption spectrometers. Nat. Photonics 10 , 788–795 (2016)..

Mauranyapin, N. P. et al. Evanescent single-molecule biosensing with quantum-limited precision. Nat. Photonics 11 , 477–481 (2017)..

Yu, X. C. et al. Single-molecule optofluidic microsensor with interface whispering gallery modes. Proc. Natl Acad. Sci. USA 119 , e2108678119 (2022)..

Watanabe, K. et al. Single virus detection on silicon photonic crystal random cavities. Small 18 , 2107597 (2022)..

He, L. N. et al. Detecting single viruses and nanoparticles using whispering gallery microlasers. Nat. Nanotechnol. 6 , 428–432 (2011)..

Shao, L. B. et al. Detection of single nanoparticles and lentiviruses using microcavity resonance broadening. Adv. Mater. 25 , 5616–5620 (2013)..

Wu, X. et al. Optofluidic laser for dual-mode sensitive biomolecular detection with a large dynamic range. Nat. Commun. 5 , 3779 (2014)..

Tang, S. J. et al. Single-particle photoacoustic vibrational spectroscopy using optical microresonators. Nat. Photonics 17 , 951–956 (2023)..

Jing, H. et al. Nanoparticle sensing with a spinning resonator. Optica 5 , 1424–1430 (2018)..

Frigenti, G. et al. Resonant microbubble as a microfluidic stage for all-optica l photoacoustic sensing. Phys. Rev. Appl. 12 , 014062 (2019)..

Kohler, L. et al. Tracking Brownian motion in three dimensions and characterization of individual nanoparticles using a fiber-based high-finesse microcavity. Nat. Commun. 12 , 6385 (2021)..

Zervas, M. N. et al. Hollow-bottle optical microresonators. In CLEO: Science and Innovations 2011 , JTuI14 (Optica Publishing Group, 2011).

Liao, J. & Yang, L. Optical whispering-gallery mode barcodes for high-precision and wide-range temperature measurements. Light Sci. Appl. 10 , 32 (2021)..

Liao, J. et al. Fano resonance and improved sensing performance in a spectral-simplified optofluidic micro-bubble resonator by introducing selective modal losses. Opt. Express 24 , 8574–8580 (2016)..

Bahl, G., Fan, X. D. & Carmon, T. Acoustic whispering-gallery modes in optomechanical shells. N. J. Phys. 14 , 115026 (2012)..

Bahl, G. et al. Brillouin cavity optomechanics with microfluidic devices. Nat. Commun. 4 , 1994 (2013)..

Dantuma, M., Gasteau, D. B. & Manohar, S. Photoacoustic spectrum analysis for spherical target size and optical property determination: a feasibility study. Photoacoustics 32 , 100534 (2023)..

Yang, H. M. et al. Robust classification with convolutional prototype learning. In Proc. 2018 IEEE/CVF Conference on Computer Vision and Pattern Recognition 3474–3482 (IEEE, 2018).

Yao, J. J. & Wang, L. V. Sensitivity of photoacoustic microscopy. Photoacoustics 2 , 87–101 (2014)..

Gandolfi, M., Banfi, F. & Glorieux, C. Optical wavelength dependence of photoacoustic signal of gold nanofluid. Photoacoustics 20 , 100199 (2020)..

Prost, A., Poisson, F. & Bossy, E. Photoacoustic generation by a gold nanosphere: from linear to nonlinear thermoelastics in the long-pulse illumination regime. Phys. Rev. B 92 , 115450 (2015)..

Wang, H. W., Chen, Y. S. & Zhao, Y. Understanding the near-field photoacoustic spatiotemporal profile from nanostructures. Photoacoustics 28 , 100425 (2022)..

Fathy, A. et al. Direct absorption and photoacoustic spectroscopy for gas sensing and analysis: a critical review. Laser Photonics Rev. 16 , 2100556 (2022)..

Shen, B. Q. et al. Integrated turnkey soliton microcombs. Nature 582 , 365–369 (2020)..

Friedlein, J. T. et al. Dual-comb photoacoustic spectroscopy. Nat. Commun. 11 , 3152 (2020)..

Manohar, S. & Razansky, D. Photoacoustics: a historical review. Adv. Opt. Photonics 8 , 586–617 (2016)..

Wang, L. V. & Yao, J. J. A practical guide to photoacoustic tomography in the life sciences. Nat. Methods 13 , 627–638 (2016)..

Daniels, D. E. et al. Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype. Nat. Commun. 14 , 6260 (2023)..

Sheridan, C. For hemophilia and thalassemia, a new era of ‘one-and-done’ gene therapies has arrived. Nat. Biotechnol. 40 , 1531–1533 (2022)..

Szegedy, C. et al. Intriguing properties of neural networks. In 2nd International Conference on Learning Representations , Banff, AB, Canada. 1–10 ICLR (2014).

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

No data

Related Author

No data

Related Institution

No data

⁰