Interferometric Image Scanning Microscopy for label-free imaging at 120 nm lateral resolution inside live cells

Michelle Küppers; W. E. Moerner

doi:10.1038/s41377-026-02210-y

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Interferometric Image Scanning Microscopy for label-free imaging at 120 nm lateral resolution inside live cells

Original Articles

- Interferometric Image Scanning Microscopy for label-free imaging at 120 nm lateral resolution inside live cells
- Light: Science & Applications Vol. 15, Issue 5, Pages: 1476-1488(2026)
- Affiliations：
  
  1.Department of Chemistry, Stanford University, Stanford, CA, USA
  2.Department of Applied Physics, Stanford University, Stanford, CA, USA
- Author bio：
  
  Michelle Küppers (mkueppe@stanford.edu)
  W. E. Moerner (wmoerner@stanford.edu)
- Funds：
- DOI：10.1038/s41377-026-02210-y
  CLC：
- Received：01 October 2025，
  
  Revised：2026-01-16，
  
  Accepted：25 January 2026，
  
  Online First：27 February 2026，
  
  Published：31 May 2026
- Accepted：
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Küppers, M. & Moerner, W. E. Interferometric Image Scanning Microscopy for label-free imaging at 120 nm lateral resolution inside live cells. Light: Science & Applications, 15, 1476-1488 (2026).
DOI：

Küppers, M. & Moerner, W. E. Interferometric Image Scanning Microscopy for label-free imaging at 120 nm lateral resolution inside live cells. Light: Science & Applications, 15, 1476-1488 (2026). DOI： 10.1038/s41377-026-02210-y.

摘要

Abstract

Light microscopy remains indispensable in life sciences for visualizing cellular structures and dynamics in live specimens. Yet

conventional fluorescence imaging can suffer from phototoxicity

limited labeling efficiency

or perturbation of biological function. Label-free techniques such as interferometric scattering microscopy (iSCAT) offer a powerful alternative by detecting nanoscale structures based on their light scattering

without the need for dyes or genetic tags. iSCAT has enabled high-sensitivity detection of single proteins and viruses on clean surfaces. More recently

its application to live cells has been extended by using confocal illumination and detection

allowing suppression of out-of-focus light

yielding subcellular structures with high contrast. This development laid the foundation for biologically relevant label-free imaging. Here

we introduce interferometric image scanning microscopy (iISM). This next-generation technique combines interferometric detection with image scanning microscopy to achieve about 120 nm lateral resolution while operating at tenfold lower incident illumination power per diffraction limited spot

significantly reducing photodamage while enhancing signal-to-noise and contrast. Using iISM

we are able to visualize intracellular organelles such as the endoplasmic reticulum

actin cytoskeleton

mitochondria

and vesicles in live cells at essentially unlimited observation times. Importantly

iISM can be readily combined with confocal fluorescence microscopy

enabling correlation of label-free dynamics and structural information with molecular specificity. Our approach opens new avenues for studying dynamic biological processes

such as host-pathogen interactions

intracellular trafficking

or cytoskeletal rearrangements

under label-free

near-native conditions. iISM thus offers a powerful new tool for high-resolution

low-impact imaging of live cells

paving the way for new biological insights.

关键词

Keywords

references

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