New microscopy method achieves angstrom-scale localization precision with one laser
Researchers in the lab of Sam Peng, the Pfizer Inc.–Gerald Laubach Career Development Assistant Professor of Chemistry at MIT and a core institute member of the Broad Institute of MIT and Harvard, have developed a super-resolution imaging technology. It allows scientists to visualize molecular structures with angstrom-level localization precision—three orders of magnitude beyond the nanometer-scale limits of standard fluorescent dyes—while simplifying the imaging process.
Unlike traditional dyes that fade rapidly under illumination and limit data collection, the platform, called U-STORM (Upconversion-enabled Stochastic Optical Reconstruction Microscopy), uses a new class of compositionally engineered upconverting nanoparticles (UCNPs) that blink spontaneously and indefinitely.
This work represents a shift in both optical materials and biological imaging. An open-access description of the study was published July 27 in Nature Nanotechnology.
Overturning a decades-old paradigm
For decades, the scientific community widely considered upconverting nanoparticles to be completely photostable and nonblinking. Because localization-based super-resolution microscopy techniques like STORM rely entirely on the stochastic "blinking" (switching between "on" and "off" states) of light emitters to distinguish closely packed molecules, UCNPs were historically deemed unsuitable for this type of imaging.
"Our laboratory has long been interested in overcoming these limitations," Peng says. "Our work began with a question: Can we develop a super-resolution imaging platform that is simultaneously long-term, multicolor, simple to operate, and capable of achieving extremely high localization precision without using imaging buffers or additional optical control?"
By meticulously controlling nanoparticle composition, the MIT and Broad Institute team discovered that these small (~10 nm) core-shell particles could be coaxed into spontaneous blinking under continuous near-infrared excitation. This blinking behavior continues indefinitely without the need for complex imaging buffers, oxygen scavengers or external optical modulation.
U-STORM's key breakthroughs
An angstrom is a tiny unit of measurement used by chemists to measure sizes and distances at the atomic level. U-STORM's ability to blink indefinitely has allowed researchers to collect more than 88,000 localization events from the same particle, sharpening localization precision to an unprecedented 0.6 Å.
Unlike conventional multicolor super-resolution imaging, which requires multiple expensive lasers and meticulous optical alignment, U-STORM can operate with just one near-infrared laser, which simultaneously excites nanoparticles emitting different colors. This reduces an experiment's complexity.
To obtain images with multiple colors, rather than capturing images sequentially over multiple rounds, U-STORM captures multiple colors simultaneously. Researchers have successfully demonstrated this by mapping epidermal growth factor receptor dimers and multimers in biological samples under physiological conditions without specialized imaging buffers.
Broader impact
Beyond expanding the boundaries of microscopy, this research establishes a new design principle for lanthanide nanomaterials. The team is already working to expand the color palette, make the particles even smaller and brighter, and deploy U-STORM to investigate complex nanoscale protein organizations and cellular signaling pathways.
Ultimately, U-STORM promises to provide laboratories worldwide with an accessible, easy-to-implement and powerful route toward high-precision molecular imaging.
Publication details
Saptarshi Mandal et al, Spontaneous and indefinite blinking in upconverting nanoparticles for ångström-precision multicolour super-resolution imaging, Nature Nanotechnology (2026). DOI: 10.1038/s41565-026-02233-x
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