In this study, the skin penetration and cellular uptake of amorphous silica particles with positive and negative surface charge and sizes ranging from 291 ± 9 to 42 ± 3 nm were investigated. Dynamic light scattering measurements and statistical analyses of transmission electron microscopy images were used to estimate the degree of particle aggregation, which was a key aspect to understanding the results of the in vitro cellular uptake experiments. Despite partial particle aggregation occurring after transfer in physiological media, particles were taken up by skin cells in a size-dependent manner. Functionalization of the particle surface with positively charged groups enhanced the in vitro cellular uptake. However, this positive effect was contrasted by the tendency of particles to form aggregates, leading to lower internalization ratios especially by primary skin cells. After topical application of nanoparticles on human skin explants with partially disrupted stratum corneum, only the 42 ± 3 nm particles were found to be associated with epidermal cells and especially dendritic cells, independent of their surface functionalization. Considering the wide use of nanomaterials in industries and the increasing interest for applications in pharmaceutics and cosmetics versus the large number of individuals with local or spread impairment of the skin barrier, e.g., patients with atopic dermatitis and chronic eczema, a careful dissection of nanoparticle-skin surface interactions is of high relevance to assess possible risks and potentials of intended and unintended particle exposure.

A concept for the growth of silica shells with a thickness of 5–250 nm onto oleate-coated NaYF4:Yb3+/Er3+ upconversion nanoparticles (UCNP) is presented. The concept enables the precise adjustment of shell thicknesses for the preparation of thick-shelled nanoparticles for applications in plasmonics and sensing. First, an initial 5–11 nm thick shell is grown onto the UCNPs in a reverse microemulsion. This is followed by a stepwise growth of these particles without a purification step, where in each step equal volumes of tetraethyl orthosilicate and ammonia water are added, while the volumes of cyclohexane and the surfactant Igepal® CO-520 are increased so that the ammonia water and surfactant concentrations remain constant. Hence, the number of micelles stays constant, and their size is increased to accommodate the growing core–shell particles. Consequently, the formation of core-free silica particles is suppressed. When the negative zeta potential of the particles, which continuously decreased during the stepwise growth, falls below −40 mV, the particles can be dispersed in an ammoniacal ethanol solution and grown further by the continuous addition of tetraethyl orthosilicate to a diameter larger than 500 nm. Due to the high colloidal stability, a coalescence of the particles can be suppressed, and single-core particles are obtained. This strategy can be easily transferred to other nanomaterials for the design of plasmonic nanoconstructs and sensor systems.

Upconversion nanoparticles (UCNPs), consisting of NaYF4 doped with 18% Yb and 2% Er, were coated with microporous silica shells with thickness values of 7 ± 2 and 21 ± 3 nm. Subsequently, the negatively charged particles were functionalized with N-(6-aminohexyl)-3-aminopropyltrimethoxysilane (AHAPS), which provide a positive charge to the nanoparticle surface. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements revealed that, over the course of 24h, particles with thicker shells release fewer lanthanide ions than particles with thinner shells. However, even a 21 ± 3 nm thick silica layer does not entirely block the disintegration process of the UCNPs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and cell cytometry measurements performed on macrophages (RAW 264.7 cells) indicate that cells treated with amino-functionalized particles with a thicker silica shell have a higher viability than those incubated with UCNPs with a thinner silica shell, even if more particles with a thicker shell are taken up. This effect is less significant for negatively charged particles. Cell cycle analyses with amino-functionalized particles also confirm that thicker silica shells reduce cytotoxicity. Thus, growing silica shells to a sufficient thickness is a simple approach to minimize the cytotoxicity of UCNPs.

Upconversion nanoparticles (UCNP) consisting of NaYF₄ doped with 18% Yb and 2% Er were coated with microporous silica shells of 7±2 nm and 21±3 nm thickness. Subsequently, the initially negatively charged particles were optionally functionalized with N-(6-aminohexyl)-aminopropyltrimethoxysilane (AHAPS), providing a positive charge onto the nanoparticle surface. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements revealed that the particles with the thicker shells release fewer lanthanide ions in 24 h than particles with a thinner shell but that even a 21±3 nm thick silica layer does not entirely block the disintegration process of the UCNP. MTT tests and cell cytometry measurements with macrophages (RAW 264.7 cells) indicate that the cells treated with amino-functionalized particles with a thicker silica shell have higher viability than those incubated with UCNP with a thinner silica shell even if more particles with a thicker shell are taken up. This effect is less significant for negatively charged particles. A cell cycle analysis with amino-functionalized particles also confirms that a thicker silica shell reduces the cytotoxicity. Thus, growing silica shells of sufficient thickness is a simple approach to minimize the cytotoxicity of UCNP.

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