Surface Engineering of Organosilica Nanoparticles Modulates Cellular Uptake, Cytotoxicity, and Mechanobiological Responses

Background/Objectives: Surface chemistry is a major determinant of nanoparticle–cell interactions, yet their influence on mechanobiological properties of cells remains incompletely understood. This study investigated the cytotoxic and mechanobiological effects of thiolated and PEGylated organosilica nanoparticles and evaluated whether cortical stiffness could serve as a complementary measure of nanoparticle–cell interactions. Methods: We evaluated thiolated organosilica nanoparticles (Si NP-SH) and two PEGylated nanoparticles (Si NP-PEG750 and Si NP-PEG5000) in non-cancerous human pulmonary fibroblasts (HPF) and cancerous human pulmonary adenocarcinoma (A549) cells. We assessed cellular viability and nanoparticle uptake after exposure and used atomic force microscopy to measure cellular cortical stiffness. Additionally, nanoparticle effects on neuroblast proliferation and mitotic progression were examined in Drosophila melanogaster larval brain explants. Results: HPF cells were markedly less sensitive to all nanoparticle formulations across the tested concentration range, whereas A549 cells showed dose-dependent sensitivity, with thiolated nanoparticles producing the earliest and greatest reduction in viability. Despite a comparable uptake of Si NP-SH and Si NP-PEG750, the thiolated nanoparticles produced greater toxicity, whereas Si NP-PEG5000 showed lower uptake but intermediate toxicity. Atomic force microscopy measurements demonstrated significant cortical softening in Si NP-SH-treated A549 cells, while HPF cells were unaffected. All nanoparticles reduced Drosophila melanogaster neuroblast proliferation in a similar order: Si NP-SH > Si NP-PEG750 > Si NP-PEG5000. Conclusions: The biological activity of organosilica nanoparticles is predominantly dependent on accessibility and intracellular reactivity of surface thiols rather than uptake alone. PEGylation shields thiol reactivity, with higher PEG molecular weight additionally reducing nanoparticle uptake. The consistency of viability, uptake, cortical stiffness, and neuroblast proliferation identifies AFM-derived cortical stiffness as a valuable complementary measurement of nanoparticle-induced stress.