Intracellular refractive index imaging via plasmonic metasurfaces

Intracellular components such as the nucleus, cytoplasm, and membrane have different optical densities, but their contrasts are too weak to be resolved using conventional optical microscopy, thus often requiring molecular staining. We here present a lithography-free plasmonic metasurface for staining-free intracellular imaging based on the intrinsic refractive index contrast of organelles, observed through nanogap plasmonic coupling. The plasmonic metasurface is constructed by electrostatic assembling oligomeric nanoparticles on a wafer-scale metallic mirror, separated with a dielectric nanospacer. The resulting metasurface exhibits uniform plasmonic resonance across the entire wafer, allowing clear visualization of intracellular structures on it with high scattering contrast. In particular, we observe 3T3-L1 cells cultured on the metasurface, which clearly visualize different optical signals from subcellular regions such as the nucleus and cytoplasm, reflecting their refractive index differences. This scalable, label-free platform provides an efficient way to visualize and analyze intracellular morphology and composition without chemical modification, suggesting a new pathway for highthroughput living cell imaging and quantitative biological analysis.