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(MAPK) pathways (Liu et al. 2015). Curcumin‐loaded SeNPs (Cur‐SeNPs) were reported to enhance the antitumor effect. In vitro results showed that Cur‐SeNPs were most effective against colorectal carcinoma cells (HCT116) and had pleiotropic anticancer effects primarily associated with increased levels of autophagy and apoptosis. On the other hand, in vivo studies on the Ehrlich's carcinoma model showed that Cur‐SeNPs significantly reduced the tumor progression and increased average survival time in mice (Kumari et al. 2017).

      Paclitaxel (PTX) represents one of the most effective natural anticancer drugs. Bidkar et al. (2017) developed SeNPs for PTX delivery and estimated its antiproliferative efficacy against cancer cells in vitro. SeNPs doped with antitumor agent PTX showed significant antiproliferative activity against cancer cells causing apoptosis associated with cell cycle arrest in G2/M phase. To increase anticancer activity of oridonin peptide – conjugated GE11 SeNPs (GE11‐SeNPs) aimed at EGFR – overexpressing cancer cells were synthesized. It was found that GE11‐SeNPs increased the cellular uptake of oridonin in cancer cells which leads to increased inhibition of tumor cell growth and reduction of toxicity toward normal cells (Pi et al. 2017). Targeted co‐delivery of epirubicin (EPI, an anticancer agent) and NAS‐24 aptamer (inducer of apoptosis) into cancer cells using SeNPs to enhance tumor response in vitro and in vivo was performed by Jalalian et al. (2018). A significant reduction in toxicity in non‐target cells and inhibition of tumor growth in mice compared to the use of epirubicin was recorded.

      The use of small interfering RNA (siRNA) for cancer therapy is one of the promising modern trends. However, the traditionally used viral carriers of siRNA are prone to have immunogenicity and the risk of mutagenesis. The creation of hyaluronic acid‐coated SeNPs and polycationic polymers polyethylenimine was an innovative approach. SiRNA was loaded onto the surface of the nanoparticles through an electrostatic interaction between siRNA and polycationic polymers polyethylenimine. The resulting particles, due to the active effect on the tumor, mediated by hyaluronic acid, penetrated HepG2 cells mainly by clathrin‐mediated endocytosis. HepG2 cell cycle arrest in the G0/G1 phase and apoptosis in the tumor were caused, and they were practically nontoxic to the key organs of mice (Xia et al. 2018c).

2.5 Nanoselenium for Alzheimer's Disease

      The main causes of Alzheimer's disease are the accumulation of amyloid protein in the brain and the formation of extracellular amyloid plaques. Nowadays, a great deal of attention has been given on the promising use of selenium in nanoform for the treatment of Alzheimer's disease. Preliminarily, it was shown that small‐sized SeNPs (5–15 nm) deplete the formation of amyloid β by reducing the production of ROS, which may be promising in Alzheimer's disease treatment (Nazıroğlu et al. 2017).

Huo et al. (2019) used SeNPs embedded into poly‐lactide‐co‐glycolide composites for Alzheimer's disease treatment. This system was reported to reduce the load of amyloid‐β in brain samples using transgenic mice (5XFAD) and significantly reduced the memory deficit in model mice. The authors visualized specific linking of curcumin‐loaded nanospheres to amyloid plaques by fluorescence microscopy (Huo et al. 2019). Similarly, Sialic acid (SA) modified SeNPs coated with a high‐penetration peptide for the hematoencephalic barrier, i.e. the peptide‐B6 (B6‐SA‐SeNPs), showed high permeability for the hematoencephalic barrier, and can act as a new nanoplatform for Alzheimer's disease treatment. The inhibitory effect of B6‐SA‐SeNP on amyloid aggregation has been demonstrated in PC12 and bEnd3 cells (Yin et al. 2015). Further, Yang et al. (2018) demonstrated that inclusion of resveratrol antioxidant into SeNPs can be promisingly used for the management of Alzheimer's disease (Yang et al. 2018). Therefore, both using SeNPs themselves and using nanoselenium as a drug delivery system is a promising field for developing alternative approaches for Alzheimer's disease treatment.

2.6 Antibacterial Activity of Nanoselenium

      Selenium nanocomposites have attracted considerable attention in terms of their antimicrobial activity. It was shown that SeNPs inhibited growth of a variety of bacteria such as Pseudomonas aeruginosa, Streptococcus aureus, and Streptococcus pyogenes in concentration of 100 μg ml⁻¹, but Escherichia coli was of 250 μg ml⁻¹. Moreover, it was found that SeNPs at concentrations of 500 μg ml⁻¹ inhibit growth of pathogenic fungi like Aspergillus clavatus (Srivastava and Mukhopadhyay 2015). In another study, it was found that SeNPs synthesized with Enterococcus faecalis can be effectively used to prevent and treat infections caused by S. aureus (Shoeibi and Mashreghi 2017).

      It was demonstrated that antimicrobial activity of SeNPs depends on the method of their synthesis and also on their size. It was found that SeNPs synthesized by the biological (green synthesis) methods usually have greater antimicrobial activity compared to chemically synthesized nanoparticles (Cremonini et al. 2016; Piacenza et al. 2017). Selenium nanocomposites synthesized using Aspergillus orayzae with average size of 55 nm were found to be effective against Acinetobacter calcoaceticus, S. aureus, and Candida albicans (Mosallam et al. 2018). Similarly, SeNPs synthesized using gram‐negative (Stenotrophomonas maltophilia) and gram‐positive (Bacillus mycoides) bacteria were reported active at low minimal inhibitory concentrations (MICs) against P. aeruginosa clinical isolates, but they did not inhibit clinical fungi isolates such as C. albicans and Candida parapsilosis. These biogenic nanocomposites demonstrated a stronger antimicrobial effect than synthetic SeNPs (Cremonini et al. 2016, 2018). SeNPs stabilized with polyvinyl alcohol showed strong growth inhibition against S. aureus at a concentration of 1 ppm, but they did not inhibit growth of E. coli (Tran et al. 2016). Lara et al. (2018) demonstrated the antifungal effect of SeNPs and chitosan against C. albicans.

      Moreover, SeNPs obtained through laser ablation in water have MIC of 50 ppm in case of E. coli and S. aureus. However, minimum bactericidal concentration (MBC) toward E. coli and S. aureus was found to be 107 ± 12 and 79 ± 4 ppm, respectively (Guisbiers et al. 2016), but for C. albicans MIC was recorded as 25 ppm (Guisbiers et al. 2017). Using electron microscopy, it was observed that SeNPs can easily stick to the biofilm and then penetrate into the pathogen and damage their cellular structure, replacing sulfur (Guisbiers et al. 2017). Therefore, it is strongly believed that selenium can be promisingly used as an effective antibacterial drug including multidrug‐resistant organisms (Shurygina et al. 2011, 2015,b, 2016; Fadeeva et al. 2015).

2.7 Nanoselenium in Diabetes Treatment

SeNPs not only counteract oxidative stress but also have hypoglycemic activity and hence can be used as hypoglycemic agents. Thus, both type 1 and type 2 diabetes can be treated with SeNPs by reducing the oxidative damage of macromolecules and increasing insulin sensitivity. The hypoglycemic effect of SeNPs in rats with diabetes induced by streptozotocin (a model of type 1 diabetes) was investigated. In rats with diabetes, there was a significant decrease in blood glucose levels in fasting state after treatment with SeNPs was recorded when SeNPs were given orally for 28 days. The concentration of insulin in the serum of these animals was also found to be higher than in non‐treated rats. It confirmed that SeNPs were able to reduce hepatic cytolysis and renal dysfunction, total lipids, total cholesterols, triglyceride levels, and low‐density lipoprotein cholesterol. In addition, SeNPs reduced the intensity of morphological disorders in liver and kidney tissues of rats. Further, the obtained findings showed that SeNPs may reduce the manifestations of hyperglycemia and hyperlipidemia in patients with diabetes, possibly causing an insulin‐like effect (Al‐Quraishy et al. 2015).

      Liu et al. (2018) investigated the antidiabetic activity of SeNPs loaded with Catathelasma ventricosum polysaccharides in mice with diabetes induced by streptozotocin. These nanocomposites showed a potential antidiabetic efficacy which was established by studying the serum profiles of glucose levels and antioxidant enzymes. In addition, SeNPs had significantly higher antidiabetic activity than other drugs of organic and nonorganic selenium (Liu et al. 2018). This study was in accordance with the observation recorded by Zeng et al. (2018). The authors demonstrated that chitosan‐stabilized SeNPs at a selenium dose of 2.0 mg kg⁻¹

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