A model of the fate of colloidal silica in the dermis was designed based on the diffusion of fluorescent silica nanoparticles through collagen hydrogels. The diffusion process was found to depend on particle size (10–200 nm) and surface charge, as well as on collagen concentration (1.5–5 mg mL−1). The presence of human dermal fibroblasts within the hydrogels also significantly impacted on the behaviour of the particles. In particular, the simultaneous monitoring of particulate and soluble forms of silica showed that both the hydrogel network and the cellular activity have a strong influence on the solubilization process of the silica particles, through a combination of surface sorption, uptake and intracellular dissolution. Interactions between silica and collagen in 3D environments also lower the cytotoxicity of 10 nm particles compared to traditional 2D cultures. The results emphasize the complexity of silica chemistry in living tissues and specifically indicate the need for further investigations of the in vivo behaviour of its soluble forms.