Membrane-Associated Phototoxicity of Silica-Coated Gold Nanostars in Colorectal Cancer Cells

Abstract Plasmonic gold nanostars are promising photoactivatable platforms for cancer therapy, but their biological performance depends not only on light-to-heat conversion but also on how they interact with cellular interfaces before irradiation. Herein, we investigated silica-coated gold nanostars (AuNS@SiO2) as NIR-responsive nanostructures in two colorectal cancer cell models, Caco-2 and HT-29, combining cellular assays with cell-derived Langmuir lipid models. AuNS@SiO2 exhibited a plasmonic band centered at 810 nm, positive ζ-potential (+32.62 mV), and preserved photothermal activity, reaching 38.56 ± 1.79 °C under 810 nm irradiation, with a temperature increase of 14.71 ± 1.16 °C. In Caco-2 cells, AuNS@SiO2 showed limited dark toxicity up to 160 μg mL–1, with cell viability remaining above 94%, whereas NIR irradiation sharply reduced viability to 14.9 and 4.82% at 267 and 400 μg mL–1, respectively. In contrast, HT-29 cells were more sensitive to AuNS@SiO2 in the absence of irradiation, with viability decreasing to 38.0 and 28.1% at the same concentrations, indicating a stronger contact-associated response. Cell-derived Langmuir lipid models supported this interpretation: at 30 mN m–1, AuNS@SiO2 induced larger relative area expansions in HT-29 models, reaching 34.87 ± 1.04% at the 1:1 ratio, compared with 17.67 ± 1.16% for Caco-2. FTIR analysis showed that nanoparticle interaction mainly affected polar headgroup and interfacial regions, while the lipid acyl-chain region remained largely preserved. Together, these findings indicate that AuNS@SiO2 elicit cell-line-dependent phototoxic profiles associated with membrane-related interactions, with Caco-2 displaying a predominantly light-amplified response and HT-29 showing a more contact-dominated response.