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). Here, we demonstrate that coupled nanostar subpopulations dominate the ensemble-average SERRS response of the suspension and that 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, revealing significantly weaker SERRS from monomeric nanoparticles compared to 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 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 SERRS amplification. However, when cells were treated with AuNStar-SiO₂ under near-neutral and acidic conditions, the opposite trend in SERRS signal was observed. At pH 7.4, the SERRS signal was suppressed even though transmission electron microscopy images of intracellular nanoparticles showed progressive extents of silica hydrolysis, while at pH 6.4 the SERRS signal was strong and the silica shell of intracellular nanoparticles remained intact. Together, these findings reveal how local environmental factors govern silica nanoshell stability and SERRS signal output in biological environments. Our results highlight a previously underappreciated role of silica hydrolysis in governing nanoparticle performance and point to new opportunities to deliberately harness or control silica nanoshell degradation in the design of silica-coated plasmonic probes for biomedical applications. Furthermore, because silica shells are widely used as linker layers for incorporating targeting functionalities, these findings raise critical questions about how in situ hydrolysis may influence key nano-bio interactions, including targeting efficiency and endocytic uptake, in established nanoparticle systems.