The approach, described by Ahmed H. Shaib, Mahmoud M. Alawieh and Stefan O. Rizzoli in Nature Protocols, combines one-step nanoscale expansion microscopy with fluctuation-based super-resolution analysis. The resulting workflow, called ONE microscopy, is intended to make molecular-scale imaging more accessible to laboratories that do not have access to cryo-electron microscopes or specialized high-end optical systems.

Traditional light microscopy is limited by diffraction, a physical effect that causes light from two nearby objects to blur together when they are too close. Even modern super-resolution methods can require complex instruments, intense labeling strategies or extensive computational processing. Expansion microscopy takes a different route. Researchers anchor biological molecules within a swellable polymer network and then expand the material, increasing the physical distance between fluorescent labels.

The expansion step does not automatically reveal every molecular detail. A protein’s structure can still be represented by only a small number of fluorescent signals, and conventional images may contain noise, background fluorescence and motion-related fluctuations. ONE microscopy addresses these limitations by analyzing changes in fluorescence intensity over time. These fluctuations contain information about the presence, position and behavior of labeled molecules that may not be obvious in a single frame.

In practical terms, the method links chemical preparation, physical enlargement and computational analysis into a single workflow. Samples are embedded in a polymer gel, labeled to identify the proteins of interest and then expanded. After expansion, researchers acquire image sequences using conventional fluorescence equipment. Specialized software analyzes the temporal variation in the recorded signals, extracting spatial information beyond what a standard diffraction-limited image would provide.

This combination is significant because it shifts the focus from simply locating a protein to examining its overall shape. For many biological questions, knowing that a protein is present is not enough. Its size, orientation and structural organization can determine how it interacts with membranes, vesicles, organelles or neighboring proteins. Directly observing those features could help researchers investigate molecular machines in their native cellular environments rather than relying exclusively on purified samples or averaged structural models.

The protocol is designed to work across a broad range of biological materials, including purified proteins, cultured cells and tissues. That flexibility could make the technique useful for researchers studying protein organization at multiple scales. A purified protein might provide a controlled test of shape reconstruction, while cells and tissues could reveal how the same protein is arranged amid the crowded and complex environment of living biology.

A major part of the reported advance is the accompanying software package. Fluctuation-based imaging can be powerful, but its usefulness depends on reliable data processing, and computational analysis has often been a barrier for non-specialist users. The authors present the software as stable and user-friendly, with the goal of making the analysis more efficient, reproducible and practical for laboratories using standard fluorescence microscopes.

ONE microscopy does not replace cryo-electron microscopy, which remains capable of resolving structures at atomic or near-atomic scales under appropriate conditions. Nor does it eliminate the challenges associated with labeling, gel chemistry, image quality and sample preparation. Expansion can introduce distortions, and successful imaging depends on preserving the relationship between the fluorescent labels and the underlying structures. Nevertheless, the method offers a complementary strategy: rather than averaging thousands or millions of molecules, it aims to examine individual protein shapes through expanded, fluorescence-labeled specimens.

The researchers describe the workflow as a practical framework for protein imaging on conventional equipment. By combining physical separation of fluorophores with information extracted from fluorescence fluctuations, the method brings nanoscale structural analysis closer to routine biological imaging. Its broader impact may come not from replacing existing forms of super-resolution, but from making a previously specialized capability more reproducible and attainable for laboratories investigating how individual proteins operate inside cells and tissues.

Subject of Research: One-step nanoscale expansion microscopy for visualizing individual protein shapes using conventional fluorescence microscopes.

Article Title: ONE microscopy.

Article References: Shaib, A.H., Alawieh, M.M. & Rizzoli, S.O. ONE microscopy. Nature Protocols (2026). https://doi.org/10.1038/s41596-026-01399-x

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41596-026-01399-x

Keywords: expansion microscopy, ExM, nanoscale imaging, super-resolution microscopy, fluctuation-based analysis, protein structure, fluorescence microscopy, single-protein imaging, cryo-electron microscopy, biological imaging

Terahertz light, situated between microwave and infrared frequencies on the electromagnetic spectrum, oscillates at an extraordinary rate of over a trillion cycles per second. These oscillation frequencies closely correspond to the natural vibrational frequencies of atoms and electrons within various materials, rendering terahertz radiation a potentially ideal probe for capturing intrinsic quantum motions. However, the relatively long wavelengths of terahertz waves—hundreds of microns in length—have historically precluded their use in high-resolution microscopy. This diffraction limit dictates that the minimum achievable focus size for any electromagnetic wave is constrained by its wavelength, thus hampering the ability to resolve features smaller than tens of microns when employing terahertz illumination.

MIT’s innovative solution hinges on the utilization of spintronic terahertz emitters—composite multilayer metallic structures that produce ultrashort, intense pulses of terahertz radiation upon laser excitation. By positioning a microscopic sample in immediate proximity to the emitter, the researchers effectively confined the terahertz electromagnetic field within subwavelength dimensions, thereby compressing the radiation into a spatially localized hotspot far below the standard diffraction limit. This proximity-induced confinement enabled the team to interact strongly with microscopic quantum states and extract signals that embody the subtle electron dynamics within materials like bismuth strontium calcium copper oxide (BSCCO), a prominent layered high-temperature superconductor.

BSCCO, renowned for its relatively elevated superconducting transition temperature, served as an ideal candidate for demonstrating this terahertz microscope’s capabilities. When cooled to near absolute zero, the researchers transmitted tightly confined terahertz pulses into an atomically thin BSCCO sample and monitored the resultant electromagnetic responses. They discovered a striking dynamic: a frictionless “superfluid” of superconducting electrons collectively oscillating at terahertz frequencies. These oscillations manifested as modulations or distortions in the reflected terahertz signal, indicating that the sample was not merely a passive medium but an active emitter of terahertz waves induced by internal quantum mechanical excitations.

Prior to this work, such collective electron oscillations within superconductors had been predicted theoretically but remained experimentally elusive due to the spatial and temporal scales involved. The terahertz superfluid plasmon, as it is termed, exemplifies a new quantum mode of coherent electron flow that exhibits zero resistance and could hold the key to unraveling the fundamental physics underpinning high-temperature superconductivity. Observing these modes directly opens potential avenues for engineering materials with enhanced superconducting properties, possibly bringing the longstanding dream of room-temperature superconductors closer to reality.

A central challenge the team overcame was the mitigation of background noise and interference from the optical pump laser used to excite the spintronic emitters. To achieve this, the experimental setup incorporated a sophisticated Bragg mirror, a multilayered reflective filter designed to selectively transmit terahertz frequencies while blocking detrimental shorter-wavelength laser light. This intricate design safeguarded the sample and ensured that the emitted terahertz pulses maintained coherence and spectral purity, critical factors for accurate imaging at such finely resolved scales.

Beyond its profound implications for fundamental physics, this terahertz microscopy technique holds transformative potential for applied sciences and emerging technologies. Terahertz frequencies are poised to revolutionize wireless communication by providing dramatically faster data transmission rates and enhanced bandwidth compared to current microwave-based systems. However, the development of devices capable of efficiently emitting and detecting terahertz radiation remains a technological frontier. The ability to image interactions between terahertz waves and microscopic device components promises to accelerate the design and optimization of next-generation terahertz antennas, sensors, and circuits, facilitating future advancements in telecommunications infrastructure.

Moreover, the nonionizing nature of terahertz radiation, combined with its capacity to penetrate a diverse array of nonmetallic materials—including fabrics, plastics, ceramics, and biological tissues—renders it a compelling candidate for safe, noninvasive imaging applications. Potential uses range from security screening systems capable of discerning concealed objects to medical diagnostic tools that visualize soft tissue anomalies without harmful ionizing radiation exposure. The enhanced spatial resolution provided by MIT’s terahertz microscope could refine these imaging techniques, enabling detailed characterization at cellular or molecular levels.

The research team comprises a collaborative ensemble of physicists and materials scientists, including lead author Alexander von Hoegen and Nobel-winning Donner Professor of Physics Nuh Gedik, alongside other MIT experts and international partners from Harvard University, the Max Planck Institutes, and Brookhaven National Laboratory. Their collective expertise spans quantum physics, spintronics, and advanced microscopy, facilitating this interdisciplinary breakthrough that fuses cutting-edge quantum materials science with state-of-the-art photonics engineering.

This work not only heralds a new era in terahertz spectroscopy but also exemplifies how overcoming fundamental physical constraints can unlock entirely new vistas in the study of complex quantum systems. By successfully imaging the coordinated terahertz oscillations of superconducting electrons, MIT researchers have illuminated a hidden layer of material behavior that had, until now, remained a theoretical abstraction. The implications ripple outward, promising future discoveries in two-dimensional quantum materials, novel device architectures, and enhanced control over electromagnetic phenomena at terahertz frequencies.

Looking ahead, the team plans to extend their investigations to a wider range of two-dimensional and layered materials, seeking to capture and characterize other collective excitations such as lattice vibrations and spin dynamics that similarly unfold within the terahertz regime. These efforts will deepen understanding of emergent quantum phases and may catalyze the invention of transformative technologies based on quantum coherence and ultrafast electron dynamics. As terahertz microscopy matures, it is poised to become an indispensable tool across physics, materials science, and engineering disciplines, bridging the gap between quantum theory and observable phenomena at microscopic scales.

In sum, this landmark accomplishment showcases how innovation in light-matter interaction techniques can reveal the intricate dance of electrons within superconductors—material systems that hold promise for revolutionizing energy transmission, computing, and communications. By capturing the elusive terahertz superfluid plasmon directly, MIT scientists have illuminated a new dimension of superconducting behavior, laying the groundwork for a future where quantum materials are not only understood but harnessed with precision innovation.

Subject of Research: Imaging and characterization of quantum electron dynamics in layered high-temperature superconductors using terahertz microscopy.

Article Title: “Imaging a terahertz superfluid plasmon in a two-dimensional superconductor”

Web References:
DOI link to article

Image Credits: Sampson Wilcox and Emily Theobald

Keywords

Electrons, Particle physics, Physics, Subatomic particles, Quantum mechanics, Mechanics, Electromagnetism, Superconductivity, Superconduction, Electromagnetic properties, Superconductors, Electrical conductors, Electrical engineering