The implementation of plasmonic nanoparticles in vivo remains hindered by important limitations such as biocompatibility, solubility in biological fluids, and physiological stability. A general and versatile protocol is presented, based on seeded emulsion polymerization, for the controlled encapsulation of gold and silver nanoparticles. This procedure enables the encapsulation of single nanoparticles as well as nanoparticle clusters inside a protecting polymer shell. Specifically, the efficient coating of nanoparticles of both metals is demonstrated, with final dimensions ranging between 50 and 200 nm, i.e., sizes of interest for bio-applications. Such hybrid nanocomposites display extraordinary stability in high ionic strength and oxidizing environments, along with high cellular uptake, and low cytotoxicity. Overall, the prepared nanostructures are promising candidates for plasmonic applications under biologically relevant conditions.

femtomolar range in the context of surface-enhanced Raman scattering (SERS) spectroscopy. [9][10][11] In addition to high sensitivity, SERS nanoparticle substrates offer high photostability, multiplexing capability, narrow peak widths, and detailed spectroscopic information about molecules adsorbed on the AuNP surface. [12][13][14][15] An essential requirement for in vivo and living cell bioimaging involves chemical and colloidal stability under bioimaging conditions. [16] Moreover, a sensitive SERS tag requires the incorporation of molecules with high Raman cross-sections, socalled Raman reporter molecules (RaRs), which exhibit strongly enhanced Raman scattering when located in close contact with plasmonic substrates with high electromagnetic (EM) near-fields upon suitable light irradiation.Spherical AuNPs, which can be produced by straightforward and scalable methods, [17,18] display localized surface plasmon resonances (LSPR) in the range of 500-600 nm, but comparatively low SERS enhancement factors in the preferred NIR spectral region for bio-applications. [19][20][21] However, when two or more plasmonic NPs are assembled and brought into close proximity, the LSPR red-shifts and local EM enhancement increases significantly at the junctions between NPs, which are known as "hot spots". [22][23][24][25] Integration of RaRs inside such hot 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 10 4 , 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.