Robust Encapsulation of Biocompatible Gold Nanosphere Assemblies for Bioimaging via Surface Enhanced Raman Scattering

Abstract Controlled assembly of gold nanoparticles (AuNPs) into clusters is a promising avenue for the development of sensitive bioimaging and diagnostic tools based on surface‐enhanced Raman scattering (SERS). However, several challenges, such as biocompatibility or colloidal and structural stability in biological environments, remain before AuNPs can be used as a tool for in vivo bioimaging. A versatile strategy for the preparation of colloidally stable and biocompatible AuNP clusters (AuNPCs) is introduced with high SERS signals, which are used as SERS contrast bioimaging agents (SERS tags). By tuning the ligand ratio of Raman reporter molecules to stabilizing polymer on the surface of each AuNP, aggregation can be carefully controlled. The resulting AuNPCs exhibit redshifted surface plasmon resonances in the near‐infrared (NIR) region, as well as distinct electromagnetic hotspots that give rise to SERS analytical enhancement factors above 10⁴, compared to non‐clustered spherical AuNPs. Thanks to the protective polymer shell, high levels of cellular uptake with low cytotoxicity are observed, allowing 3D SERS mapping of cells with sufficiently high spatial resolution to detect AuNPCs within intracellular organelles.