Plasmonic enhanced raman structured illumination microscopy

The National Institute of General Medical Sciences awarded the University of California, San Diego $1,830,401 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop plasmonic enhanced Raman structured illumination microscopy (PERSIM), a novel microscopy technique designed to improve resolution and sensitivity in label-free molecular imaging.

PERSIM combines localized plasmonic structured illumination microscopy with Raman scattering microscopy to achieve approximately 50 nanometer resolution—a fourfold improvement over the standard 200 nanometer diffraction limit of conventional Raman scattering instruments. The technique uses plasmonic nanoantennas arrays capable of supporting localized surface plasmon resonance to overcome the low signal strength inherent in conventional Raman scattering due to small scattering cross-sections. The project targets applications in biomedical imaging and biochemistry.

Work is performed at UC San Diego in La Jolla, California, with a period of performance from July 1, 2026, through June 30, 2030. Principal Investigator Liu, a new investigator to the National Institutes of Health, brings extensive expertise in high-speed and super-resolution imaging, bio-photonics, and nanoscale light manipulation through plasmonic structures. The project comprises three primary aims: designing and constructing the PERSIM system, designing and fabricating the plasmonic nanoantennas substrate for the designated wavelength range, and developing an autonomous neural network-based ultrafast image processing component.

Abstract

This project aims to develop a novel microscopy technique known as plasmonic enhanced raman structured illumination microscopy (persim) to enhance the resolution and sensitivity of raman scattering microscopy (RSM). RSM is a valuable tool for label-free imaging as IT can unveil molecular characteristics based on their vibrational fingerprints. However, conventional raman scattering microscopy (RSM) instruments are limited by a spatial resolution of approximately 200 NM, primarily due to the diffraction limit, and they also suffer from low signal strength due to the small raman scattering cross-section. Persim combines the strengths of localized plasmonic structured illumination microscopy (lpsim) and RSM to produce label-free images with a resolution ~50 NM, representing a fourfold improvement over standard RSM. The key innovation behind persim lies in the utilization of plasmonic nanoantennas array (PNA), capable of supporting localized surface plasmon resonance (lspr). This proposed approach holds great promise for applications in the fields of biomedical imaging and biochemistry, as IT can provide higher-resolution label-free imaging with enhanced intensity and sensitivity compared to existing RSM techniques. The PI LIU is a new investigator to NIH but has extensive expertise in pioneering high-speed and super-resolution imaging techniques, BIO-photonics, and nanoscale light manipulation through plasmonic structures. This project comprises three primary objectives. In aim 1, we will design and construct the persim system, utilizing a functional lpsim fluorescence setup and a standard SRS system from the LIU lab. Aim 2 focuses on the critical element of the PNA substrate, which must be meticulously designed and fabricated to operate effectively within the designated wavelength range of the persim system. Aim 3 involves the development of a autonomous neural network based ultrafast image reconstruction algrith for real-time imaing and the validation of the complete persim system using well-known nanoscale structures in neuronal cells. We will also make a comprehensive comparison between persim, standard stimulated raman scattering (SRS) and super-resolution fluorece imaging. The significance of this research lies in the development of persim, a groundbreaking label-free super-resolution microscopy technique poised to revolutionize the field of bioimaging. With its unprecedented spatial resolution and imaging speed, persim has the potential to catalyze new scientific breakthroughs in biology and the life sciences. IT opens exciting opportunities for research and applications across a wide range of disciplines.