Promotion of allergic immune responses by intranasally-administrated nanosilica particles in mice

With the increase in use of nanomaterials, there is growing concern regarding their potential health risks. However, few studies have assessed the role of the different physical characteristics of nanomaterials in allergic responses. Here, we examined whether intranasally administered silica particles of various sizes have the capacity to promote allergic immune responses in mice. We used nanosilica particles with diameters of 30 or 70 nm (nSP30 or nSP70, respectively), and conventional micro-sized silica particles with diameters of 300 or 1000 nm (nSP300 or mSP1000, respectively). Mice were intranasally exposed to ovalbumin (OVA) plus each silica particle, and the levels of OVA-specific antibodies (Abs) in the plasma were determined. Intranasal exposure to OVA plus smaller nanosilica particles tended to induce a higher level of OVA-specific immunoglobulin (Ig) E, IgG and IgG1 Abs than did exposure to OVA plus larger silica particles. Splenocytes from mice exposed to OVA plus nSP30 secreted higher levels of Th2-type cytokines than mice exposed to OVA alone. Taken together, these results indicate that nanosilica particles can induce allergen-specific Th2-type allergic immune responses in vivo. This study provides the foundations for the establishment of safe and effective forms of nanosilica particles

Effect of amorphous silica nanoparticles on in vitro RANKL-induced osteoclast differentiation in murine macrophages

Amorphous silica nanoparticles (nSP) have been used as a polishing agent and/or as a remineralization promoter for teeth in the oral care field. The present study investigates the effects of nSP on osteoclast differentiation and the relationship between particle size and these effects. Our results revealed that nSP exerted higher cytotoxicity in macrophage cells compared with submicron-sized silica particles. However, tartrate-resistant acid phosphatase (TRAP) activity and the number of osteoclast cells (TRAP-positive multinucleated cells) were not changed by nSP treatment in the presence of receptor activator of nuclear factor κB ligand (RANKL) at doses that did not induce cytotoxicity by silica particles. These results indicated that nSP did not cause differentiation of osteoclasts. Collectively, the results suggested that nanosilica exerts no effect on RANKL-induced osteoclast differentiation of RAW264.7 cells, although a detailed mechanistic examination of the nSP70-mediated cytotoxic effect is needed

Synthesis and Properties of Nucleobase-Sugar Dual Modified Nucleic Acids: 2<b>′</b>‑OMe-RNA and scpBNA Bearing a 5‑Hydroxycytosine Nucleobase

Naturally occurring 5-hydroxycytosine (5‑OHCyt), which is associated with DNA damage, was recently found to reduce the hepatotoxicity of antisense oligonucleotides (ASOs) without compromising its antisense activity when used as a replacement for cytosine (Cyt). Additionally, sugar-modified nucleic acids, such as 2′-O-methylribonucleic acid (2′-OMe-RNA) and 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA), have emerged as useful antisense materials. Herein, we aimed to combine these two advantages by designing dual modified nucleic acids 2′-OMe-RNA-5‑OHCyt and scpBNA-5‑OHCyt bearing the 5‑OHCyt nucleobase to develop efficient and safe ASOs. We describe the synthesis of 2′-OMe-RNA-5‑OHCyt and scpBNA-5‑OHCyt phosphoramidites and their incorporation into oligonucleotides (ONs). The duplex-forming ability and base discrimination properties of 2′-OMe-RNA-5‑OHCyt- and scpBNA-5‑OHCyt-modified ONs were similar to those of 2′-OMe-RNA-Cyt- and scpBNA-mCyt-modified ONs, respectively. We also synthesized two 2′-OMe-RNA-5‑OHCyt-modified ASOs, and one of the two was found to exhibit reduced hepatotoxicity while retaining target mRNA knockdown activity in in vivo experiments

Delivery of Oligonucleotides Using a Self-Degradable Lipid-Like Material

The world-first success of lipid nanoparticle (LNP)-based siRNA therapeutics (ONPATTRO(R)) promises to accelerate developments in siRNA therapeutics/gene therapy using LNP-type drug delivery systems (DDS). In this study, we explore the optimal composition of an LNP containing a self-degradable material (ssPalmO-Phe) for the delivery of oligonucleotides. siRNA or antisense oligonucleotides (ASO) were encapsulated in LNP with different lipid compositions. The hepatic knockdown efficiency of the target genes and liver toxicity were evaluated. The optimal compositions for the siRNA were different from those for ASO, and different from those for mRNA that were reported in a previous study. Extracellular stability, endosomal escape and cellular uptake appear to be the key processes for the successful delivery of mRNA, siRNA and ASO, respectively. Moreover, the compositions of the LNPs likely contribute to their toxicity. The lipid composition of the LNP needs to be optimized depending on the type of nucleic acids under consideration if the applications of LNPs are to be further expanded