New microscopy method achieves angstrom-scale localization precision with one laser

A groundbreaking advancement in super-resolution microscopy has been achieved by researchers at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard. A new technique known as U-STORM enables scientists to achieve angstrom-scale localization precision using a single laser, marking a major leap forward in the field of molecular imaging. The innovation, developed in the lab of Sam Peng, the Pfizer Inc, Gerald Laubach Career Development Assistant Professor of Chemistry at MIT, introduces a novel approach to super-resolution imaging. This method utilizes a unique class of upconverting nanoparticles (UCNPs) that exhibit spontaneous and indefinite blinking under continuous near-infrared excitation. Unlike traditional fluorescent dyes, which degrade quickly and limit data acquisition, these engineered nanoparticles offer enhanced stability and longevity. The technique, described in an open-access paper published on July 27 in Nature Nanotechnology, presents a transformative solution for high-precision biological imaging. For years, the scientific community believed that upconverting nanoparticles were inherently photostable and did not blink, making them unsuitable for localization-based super-resolution techniques such as STORM. These methods depend on the random switching of light emitters to differentiate closely spaced molecules. However, the MIT and Broad Institute team challenged this assumption by exploring how nanoparticle composition could influence their optical properties. Through careful manipulation of nanoparticle composition, the researchers discovered that small, ~10 nm core-shell particles could be induced to blink continuously under near-infrared excitation. This blinking persists indefinitely without requiring complex imaging buffers, oxygen scavengers, or external optical controls. This discovery overturned a longstanding belief and opened new possibilities for advanced imaging applications. One of the key advantages of U-STORM lies in its simplicity and efficiency. Traditional multicolor super-resolution imaging typically demands multiple lasers and intricate optical setups. In contrast, U-STORM operates with a single near-infrared laser, which simultaneously excites nanoparticles emitting different colors. This simplification significantly reduces experimental complexity while maintaining high-resolution capabilities. The technique’s ability to capture multiple colors simultaneously has enabled researchers to map biological structures such as epidermal growth factor receptor dimers and multimers in living cells under normal physiological conditions. These experiments were conducted without the need for specialized imaging buffers, demonstrating the practicality and robustness of the method. The implications of this research extend far beyond microscopy. By establishing a new design principle for lanthanide nanomaterials, the work opens avenues for further advancements in nanotechnology. The team is currently working to enhance the color range of the nanoparticles, increase their brightness, and reduce their size. Additionally, they aim to apply U-STORM to study complex nanoscale protein arrangements and cellular signaling pathways, potentially leading to deeper insights into biological processes at the molecular level. As the research progresses, the potential for widespread adoption of U-STORM in laboratories around the world grows. Its accessibility, ease of implementation, and high precision position it as a valuable tool for advancing scientific understanding at the atomic scale. With continued refinement, U-STORM could revolutionize the way researchers explore the intricate mechanisms underlying life at the smallest levels.