“Great Unified Microscope” Reveals Hidden Micro and Nano Worlds Inside Living Cells

University of Tokyo researchers have created a powerful new microscope that captures both forward- and back-scattered light at once, letting scientists see everything from large cell structures to tiny nanoscale particles in a single shot.

Researchers at the University of Tokyo have developed a new type of microscope that can detect signals over an intensity range 14 times broader than that of standard microscopes. The technique works label-free, meaning it does not require extra fluorescent dyes or stains. Because of this, the method is gentle on living cells and suitable for long-term monitoring, making it attractive for testing and quality control in pharmaceutical and biotechnology settings. The work is described today (November 14) in the journal Nature Communications.

Balancing Sensitivity and Scale in Modern Imaging

Microscopes have been essential tools for scientific discovery since the 16th century, but each major advance has typically required instruments that are not only more precise, but also more specialized. As a result, today's advanced imaging methods often involve difficult tradeoffs between what they can see and how they see it. Quantitative phase microscopy (QPM) uses forward-scattered light to detect structures at the microscale (in this study, over 100 nanometers), but it cannot access much smaller features.

In practice, QPM is often used to capture still images of complex cellular architecture. Interferometric scattering (iSCAT) microscopy takes a different approach by relying on back-scattered light and can pick up structures as tiny as single proteins. This makes it powerful for "tracking" individual particles and following rapid changes inside cells, but it does not offer the broad, whole-cell perspective that QPM provides.

Dual-Direction Light Measurement Strategy

"I would like to understand dynamic processes inside living cells using non-invasive methods," says Horie, one of the first authors.

Guided by this goal, the team explored whether collecting light traveling in both directions simultaneously could break the usual trade-off and capture a wide range of particle sizes and motions in a single frame. To evaluate this idea and verify that their custom-built microscope was working as intended, they focused on what happens during cell death. In one experiment, they recorded a single image that contained information from both forward- and backward-traveling light.

Separating Signals With High Precision

"Our biggest challenge," Toda, another first author, explains, "was cleanly separating two kinds of signals from a single image while keeping noise low and avoiding mixing between them."

By carefully processing the data, the researchers succeeded in measuring the movement of larger cell components (micro) as well as much smaller particles (nano). Comparing the forward- and back-scattered signals also allowed them to estimate each particle's size and its refractive index, a property that describes how strongly light bends or scatters when it encounters the particle.

Toward Imaging Exosomes and Viruses

"We plan to study even smaller particles," Toda says, already thinking about future research, "such as exosomes and viruses, and to estimate their size and refractive index in different samples. We also want to reveal how living cells move toward death by controlling their state and double-checking our results with other techniques."

Reference: "Bidirectional quantitative scattering microscopy" 14 November 2025, Nature Communications.
DOI: 10.1038/s41467-025-65570-w