Se and its organic and inorganic compounds in dietary supplements have been found to possess excellent pharmacodynamics and biological responses. However, the element in its bulk form has low bioavailability and high toxicity, which is tremendously improved upon conversion to the nanoform [16]. Various efficient methods have been reported to synthesize stable SeNPs and their functional derivatives, which generally can be summarized as physical, chemical, and biological methods (Table 1).

Physical synthesis: Commonly used physical methods for the SeNPs synthesis include hydrothermal treatments, microwave irradiation, and laser ablation [39]. For example, Nastulyavichus et al. [40] prepared SeNPs with a high-purity base coating via fast and effective nanosecond laser ablation of the corresponding solids in water, with an average particle size of ~200 nm. Similarly, Gudkov et al. [41] used fiber ytterbium laser and copper vapor laser to ablate the SeNPs in water and adjusted the particle size of SeNPs by changing the laser fragmentation time. In addition, Menazea et al. [17] synthesized polyvinyl alcohol/chitosan-doped SeNPs via one-step laser ablation, which improved the antibacterial activity of the nanoparticles. Although physical synthesis is environmentally friendly, it has problems of high energy consumption, easy contamination of samples, and uneven particle sizes [42]. For example, the laser ablation method requires a Coherent-Vitara laser oscillator to produce fs laser pulses [43].

Chemical synthesis: Chemical synthesis of SeNPs involves a redox reaction. The reducing agents, such as ascorbic acid and sodium borohydride (NaBH₄) are commonly used to cause reduction in the oxidation state, while Na₂SeO₃ or selenium dioxide (SeO₂) are used as Se sources [42]. In terms of the chemical synthesis, the morphology of the SeNPs is also dependent on the reducing agents. For example, Chandramohan et al. [44] prepared SeNPs with different morphology (rod, spherical, and square) using different reducing agents, bovine serum albumin, D-glucose, and soluble starch, respectively. The SeNPs with different morphologies exhibit different antibacterial and antioxidant properties. However, bare SeNPs have poor dispersibility and is easily oxidized. To solve the problem of chemically synthesized SeNPs easily agglomerating and their inability to exist in a stable state for a long time, surfactants, such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG) are employed. For example, Cao et al. [18] synthesized water-soluble and stable SeNPs from gray selenium using PEG as surfactants. The results showed that the synthesized SeNPs was dispersed spherically and had good stability. In short, the SeNPs with different morphology can be easily obtained from the chemical synthesis by changing the kinds of reducing agents. However, the chemical synthesis may involve toxic chemicals.

Biosynthesis strategy: Biosynthesis, also known as green synthesis, rely on plants [46], fungi [47], and bacteria to synthesize SeNPs, which possesses the advantages of being environmentally friendly, less toxic, and economical compared to other methods. For example, Xu et al. [46] synthesized SeNPs by fermentation under anaerobic conditions using the probiotic Lactobacillus casei ATCC 393 as the starting strain and Na₂SeO₃ as the selenium source. In another study, Gonzalez-Salitre et al. [48] investigated the progress of bioproduction of Se nanoparticles by probiotic yeast due to their ease of culture, lack of toxicity and pathogenicity. Fan et al. [11] realized the green synthesis of SeNPs by using rose eggplant leaf extract as the reducing agent. In another study, Miglani et al. [49] extracted SeNPs from fresh guava leaves. These studies show that biosynthesis method is not only safe and efficient but also results in SeNPs with better physical and chemical properties.

The SeNPs can be functionalized by integrating a variety of drugs or biomacromolecules based on covalent or non-covalent coupling, such as the chemical conjugation of biomacromolecules on SeNPs and the physical adsorption onto the surface SeNPs [50]. To achieve better disease treatment, signal regulation, and targeting, researchers modified and functionalized the surface of SeNPs by some functional groups with special properties (such as polyphenols [23,51,52], polysaccharides with special functional groups [24,53,54,55,56,57,58], proteins [59], etc.), therapeutic drugs (doxorubicin [60], irinotecan [38], etc.), and target genes [22].

Natural polyphenols are a class of natural molecules with two or more phenolic hydroxyl groups that are widely present in fruits, vegetables, tea, plant seeds, and Chinese herbal medicine [61]. The strong antioxidant capacity of natural polyphenols has been widely exploited in the biomedical field. In particular, polyphenols can form dynamic covalent interactions or strong non-covalent interactions between catechol/pyrogallol with other functional groups, which therefore can be easily hybridized with a variety of building groups to form multifunctional composites, further broadening their applications [19,20,21,61,62]. The combination of SeNPs and polyphenols can synergistically enhance the antioxidant properties of SeNPs and endow SeNPs with properties inherent to natural polyphenols, such as adhesion. It was confirmed that the stability and oral availability of epigallocatechin gallate modified SeNPs were improved by ascorbic acid reduction [63]. Wang et al. [25] used gallic acid (GA) to reduce and modify SeNPs, which not only overcame the shortcomings of easy oxidation of GA and instability of Na₂SeO₃, but also obtained SeNPs with improved broad-spectrum antibacterial activity. Kumari et al. [64] prepared curcumin-loaded SeNPs (Cur@SeNPs) with uniform size and anticancer effect. In another study, the resveratrol modification of SeNPs not only endowed the SeNPs with anti-oxidative activity, but also improved the binding affinity of SeNPs to amyloid-β (Aβ), which had great potential in neuroprotection [65].

Polysaccharides are the cheapest and most abundant biopolymers in the biosphere, and are formed by the natural polymerization of monosaccharides through different glycosidic bond types. Compared with other biopolymers, they are rich in reactive functional groups, such as –OH, –COOH, –NH₂ and –OSO₃, with excellent adjustable performance and different physical, chemical, and biological characteristics [19,26,27]. Polysaccharide-functionalized SeNPs also have many advantages, such as high biocompatibility, biodegradability, and active hydroxyl groups [28]. For example, SeNPs functionalized with chitosan (CS), exhibited both enhanced antioxidant and antimicrobial properties [29,56]. The SeNPs were also coupled with hyaluronic acid (HA) to form tumor targeting vector HA@SeNPs, which were then used to encapsulate paclitaxel [51]. In addition, Lentinan was used to functionalize SeNPs, which can target the mitochondria of tumor cells and induce their apoptosis of tumor cells [24]. Wang et al. [30] combined SeNPs with chestnut polysaccharide and significantly improved the antioxidant activity of chestnut polysaccharide. Yang et al. [34] constructed stable and size-controlled lichenan-modified SeNPs by chemical reduction, which also exhibited strong antioxidant activity. Rao et al. [31] developed a traditional Chinese medicine, astragalus polysaccharide (APS)-decorated SeNPs to deliver tanshinone IIA (TSIIA) (TSIIA@SeNPs-APS), which displayed enhanced antioxidant activity compared to pure SeNPs. At the same time, the results also showed that TSIIA@SeNPs-APS played a critical role in regulating selenoprotein for the treatment of spinal cord injury. Chen et al. [35] prepared SeNPs in a simple redox system using polygonatum polysaccharide (PSP) as a stabilizer. The PSP@SeNPs exhibited better protective behavior against PC-12 cell activity induced by H₂O₂ than pure SeNPs. Zhou et al. [32] successfully fabricated dextran-functionalized SeNPs, which exhibited good anticancer activity in vivo or in vitro. In addition, Tang et al. [33] prepared SeNPs using larch arabinogalactose as a stabilizer and explained the anti-tumor activity of SeNPs based on inhibiting tumor cell proliferation and internalization by tumor cells through endocytosis, which induces tumor cell apoptosis. Furthermore, multifunctional SeNPs can be achieved by the polysaccharide–polyphenol synergy have better stability, stronger antioxidant properties, and anticancer effects than the single modified SeNPs [52].

In addition to the use of polyphenols and polysaccharides to functionalize SeNPs, other functional materials have been employed to endow SeNPs with more specific properties (e.g., proteins [36], peptides [37], and drugs). For example, human serum albumin (HSA)-coated SeNPs can target mitochondria [67]. Peptide-modified SeNPs can target inflammation [68]. Polysaccharide-protein complexes wrap SeNPs, which have stronger anticancer activity [69] and can effectively promote bone formation in vitro and in vivo [70]. Deng et al. [71] prepared SeNPs using solvent diffusion/in situ reduction and loaded with the hypoglycemic drugs Mulberry leaf and Pueraria Lobata for synergistic treatment of diabetes. Xia et al. [72] also employed galactose-modified SeNPs as tumor targeting components to prepare tumor targeted delivery vector and then loaded doxorubicin onto the surface of nanomaterials to improve the anti-tumor effect of doxorubicin in the treatment of liver cancer. In addition, SeNPs can also be used as a gene vector. For instance, Xia et al. [22] prepared functional SeNPs as a non-viral tumor-targeting vector (RGDfC-SeNPs). The RGDfC (Arg-Gly-Asp-DPhe-Cys) could specifically bind to the overexpressed α_vβ₃ integrin in tumor cells, and the positively charged RGDfC could also promote ligation between nanoparticles and siRNA through their electrostatic interactions. Thus, the RGDfC-modified SeNPs was used to selectively deliver siRNA to HepG2 liver cancer cells and tissues for the treatment of hepatocellular carcinoma. In addition to the examples above, there are numerous other similar studies, and these SeNPs with unique capabilities offer further therapeutic options for a variety of illnesses.

In short, biomolecules, such as polysaccharides and polyphenols, can be used to not only stabilize the SeNPs due to their abundant hydroxyl, carbonyl, and other functional groups that interact with SeNPs, but also can be used to enhance the bioactivities of functionalized SeNPs with the synergistic effects derived from the biomolecules themselves.