BPS2026 – Subcellular toxicity modulation of silica nanoparticles: Influence of size and surface functionalization revealed by structured illumination microscopy

Silica nanoparticles (SiNPs) are widely explored in biomedical, environmental, and industrial domains owing to their intrinsic biocompatibility, tunable surface chemistry, and facile synthesis. Their versatility has supported applications ranging from drug delivery and imaging to biosensing and targeted therapeutics. However, while whole-cell responses to SiNPs have been extensively studied, their potential toxicity at the subcellular level remains largely unresolved, primarily due to the limited accessibility of nanoscale organelles. Structured illumination microscopy (SIM), with its ability to achieve super-resolution imaging under live-cell conditions, provides a powerful means to address this knowledge gap. In this study, we employed SIM to directly visualize and quantify the intracellular interactions of four classes of SiNPs—unmodified particles of 30 and 100 nm and surface-functionalized variants bearing carboxyl (–COOH) or amine (–NH 2 ) groups. Bulk cell viability assays revealed negligible cytotoxicity across all nanoparticle types, suggesting general biocompatibility. Strikingly, SIM-based organelle-level analyses uncovered pronounced subcellular perturbations induced by unmodified SiNPs, independent of particle size. In contrast, surface-functionalized SiNPs exhibited substantially reduced organelle-specific toxicity, demonstrating that chemical modification of nanoparticle surfaces can mitigate adverse biological interactions. These findings highlight the importance of integrating super-resolution imaging into nanotoxicology studies to uncover phenotypes obscured in whole-cell assays. More broadly, they emphasize that precise control over nanoparticle surface chemistry is a key determinant in designing safer and more effective SiNPs for biomedical translation.