pH-Dependent Silica Nanoshell Degradation Influences SERRS Enhancement in Biological Environments

Silica-encapsulated gold nanostars (AuNStar-SiO2) are a widely used plasmonic nanoparticle platform for surface-enhanced resonance Raman scattering (SERRS) bio-applications. In this paper, we demonstrate that coupled nanostar subpopulations can dominate the ensemble-average SERRS response of the suspension and that near-neutral standard cell culture conditions are sufficient to hydrolyze the silica nanoshell and introduce variability in signal intensity following in vitro endocytosis. Monomeric and oligomeric AuNStar-SiO2 fractions were isolated using continuous density-gradient centrifugation and monomeric populations were found to exhibit significantly weaker SERRS compared to their oligomeric counterparts. Using monomer-enriched AuNStar-SiO2, we investigated the stability of the silica nanoshell under conditions representative of sequential acidification during endocytosis and characterized the subsequent changes to nanoparticle optical properties. In acidic environments, reflecting lysosomal pH, the silica shell was stable, whereas near-neutral and alkaline conditions in cell culture medium induced silica-shell hydrolysis, nanostar release, and interparticle aggregation, leading to transient SERS amplification. When cells were treated with AuNStar-SiO2 under near-neutral and acidic conditions, we observed the opposite trend in SERS signal strength. At pH 7.4, the SERRS signal was suppressed even though transmission electron microscopy (TEM) images of intracellular nanoparticles showed progressive extents of silica hydrolysis, while at pH 6.4 SERS signal was strong and the silica shell of intracellular nanoparticles remained intact. Together, these findings show how SERRS output can differ between control conditions and biological applications, highlighting the role that local environmental factors play in nanoparticle stability and performance. Our results highlight the previously overlooked role of silica nanoshell instability on SERRS signal output in physiological environments and describe opportunities to harness silica nanoshell hydrolysis to improve the biomedical application of silica-coated plasmonic probes.