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Silica nanoparticles (SNPs) have shown promise in biomedical applications such as drug delivery and imaging due to their versatile synthetic methods, tunable physicochemical properties, and ability to load both hydrophilic and hydrophobic cargo with high efficiency. To improve the utility of these nanostructures, there is a need to control the degradation profile relative to specific microenvironments. The design of such nanostructures for controlled combination drug delivery would benefit from minimizing degradation and cargo release in circulation while increasing intracellular biodegradation. Herein, we fabricated two types of layer-by-layer hollow mesoporous SNPs (HMSNPs) containing two and three layers with variations in disulfide precursor ratios. These disulfide bonds are redox-sensitive, resulting in a controllable degradation profile relative to the number of disulfide bonds present. Particles were characterized for morphology, size and size distribution, atomic composition, pore structure, and surface area. No difference was observed between in vitro cytotoxicity profiles of the fabricated nanoparticles at 24 h in the concentration range below 100 µg mL−1. The degradation profiles of particles were evaluated in simulated body fluid in the presence of glutathione. The results demonstrate that the composition and number of layers influence degradation rates, and particles containing a higher number of disulfide bridges were more responsive to enzymatic degradation. These results indicate the potential utility of layer-by-layer HMSNPs for delivery applications where tunable degradation is desired.

Accumulation of silica nanoparticles (SNPs) in the testes leads to male reproductive toxicity. However, little is known about the effect and mechanistic insights of SNP-induced autophagy on apoptosis in Leydig cells. In this study, we aimed to verify the role of SNP-induced autophagy in apoptosis and explore the possible underlying mechanism in mouse primary Leydig cells (PLCs). H&E staining showed that SNPs changed the histological structures of the testes, including a reduction in the Leydig cell populations in vivo. CCK-8 assay showed that SNPs decreased cell viability, and flow cytometry showed that SNPs increased cell apoptosis, both in a dose-dependent manner in vitro. Additionally, Western blotting further found that SNPs activated autophagy by an increase in BECLIN-1, ATG16L, and LC3-II levels and promoted the intrinsic pathway of apoptosis by an increase in the BAX/BCL-2 ratio, cleaved the caspase 8 and caspase 3 levels. Furthermore, autophagy decreased SNP-induced apoptosis via regulation of the caspase 8 level combined with rapamycin, 3-methyladenine, and chloroquine. BECLIN-1 depletion increased the caspase 8 level, leading to an increase in SNP-induced cell apoptosis. Collectively, this evidence demonstrates that SNPs activated BECLIN-1-mediated autophagy, which prevented SNP-induced testicular toxicity via the inhibition of caspase 8-mediated cell apoptosis in Leydig cells.