Over the past decade, nanoparticles (NPs) have received much attention in various fields ranging from environmental science to medicine. Growing exploration of NPs has resulted in the identification of many unique properties of objects at the nanoscale such as magnetic, catalytic, mechanical, and many others when compared to objects at a “regular” scale made of the same material [1], [2], [3], [4]. Perhaps the most promising applications of NPs are related to biomedical research. Indeed, numerous applications are being reported already in biomedicine, such as drug-delivery agents, biosensors, and imaging contrast agents [2], [4], [5], [6], [7]. Cerium dioxide nanoparticles (CeO2 NPs) are used increasingly in nanotechnology and particularly in bioresearch [8]. The presence of shielded 4 f electrons, low redox state of Ce4+/Ce3+ pair (∼ 1.52 V), the coexistence of easily switchable oxidation states + 3 and + 4 and the presence of oxygen vacancies reflect the unique properties and the possibility of diverse uses of CeO2 NPs [8], [9], [10], [11], [12]. The Ce3+/Ce4+ ratio on the particle surface can be expressed as a function of the particle size, and, in turn, the particle size can be controlled during synthesis [13], [14]. Precise controlled physical-chemical properties of nanoparticles are essential for biomedical applications, i.e. not all methods allow fabrication of the NPs suitable for biomedicine [15], [16], [17], [18], [19], [20]. Therefore, the choice of the synthesis method for naked NPs is of great importance [21], [22], [23], [24], [25], [26]. However, the interactions at the "nano-bio" interface may be affected not only by physical-chemical properties but also by the presence of a coating on the surface of NPs [13], [17]. Modification of the NPs surface improves stability, bioavailability, biocompatibility, and solubility, but also reduces non-specific interactions with cells and individual cell components, thus, increasing their circulation time in the blood, and can significantly reduce the potential toxicity of NPs [14], [17], [27], [28], [29]. For example, very recently the reactive oxygen species-responsive CeO2 NPs decorated with 5-fluorouracil-loaded chitosan nanoparticles for enhanced anticancer activity in hepatocellular carcinoma HepG2 cells have been developed and tested [30]. However, a special place in the field of nanoparticle modification belongs to the use of highly hydrophobic components such as surfactants or phospholipids since they provide additional functions for nanoparticles [31], [32], [33]. Thus, surface modifications can play a significant role in determining the functional properties of CeO2 NPs [29], [33], [34], [35]. Recently, we demonstrated the antioxidant and anti-amyloid activity of naked CeO2 NPs prepared by precipitation in the reversal microemulsions and water-alcohol solutions [23], [24], [25], [26]. However, a much stronger ability to affect amyloid aggregation was detected for amphiphilic non-ionic surfactants, including dodecyl maltoside [36], [37], [38], [39]. n-Dodecyl-β-D-maltoside (DDM) is a non-ionic mild surfactant that consists of a hydrophilic maltose head and a hydrophobic long-chain alkyl tail. The critical micelle concentration (CMC) of DDM is 0.15–0.18 mM in water, but CMC is slightly changed when it is measured in a low pH buffer, containing 100 mM NaCl [38], [40], [41]. Unlike strong denaturing surfactants, DDM can preserve the native structure of many proteins without affecting the α-helical structure of proteins or dissociating the subunits of the multisubunit protein complexes [42], [43], [44], [45]. It has also been demonstrated that DDM in sub-micellar or micellar concentrations does not affect the native structure and conformation of insulin [36]. However, the most important for the current study is that DDM can bind to eight insulin binding sites and thus significantly modulate the morphology, degree, and kinetics of insulin amyloid formation [38]. Therefore, it is reasonable to expect that DDM-modified CeO2 NPs (CeO2 @DDM NPs) will demonstrate both, strong anti-amyloidogenic activity and antioxidant properties. It is noteworthy that the knowledge of the use of DDM for the coating of nanosized material is very limited. Although the adsorption behavior of DDM on certain surfaces (such as silica, alumina, hematite, etc.) has been studied, as far as we know, no studies have been published using DDM to modify NPs [46], [47], [48], [49], [50].

Insulin was chosen to study the anti-amyloidogenic effect of CeO2 NPs. It is a small protein consisting of two chains linked by disulfide bonds and plays a key role in blood glucose homeostasis. The importance of insulin is not limited to the use of this hormone for the treatment of diabetes, but also as an amyloid-prone protein. It is important to be noted, that insulin is not active when it aggregates (aggregates formed during its industrial production, purification, and transportation), and therefore the formation of insulin amyloid fibrils should be prevented. In addition, insulin amyloid fibrils are detected in vivo near the sites of repeated insulin injections in diabetic patients [51], [52], [53]. Notably, the aggregation of insulin has only been observed with externally administered forms of insulin, and not when it is normally produced in the human body. Moreover, an autoimmune response to insulin oligomers and fibrils in Parkinson´s patients has been observed [54]. However, as with other amyloid-prone proteins, the mechanism of amyloid protein aggregation is unknown. One of the well-accepted hypotheses is that oxidative stress is a possible trigger (or consequence) for amyloid fibril formation. In fact, it was shown that oxidative stress-induced modification of amino acids can lead to protein aggregation [55], [56], but it was also demonstrated that aggregation can initiate oxidative stress or protect proteins against oxidative damage [57], [58]. Therefore, the fabrication of new NPs associated with the generation of oxidative stress or its elimination; and capable of interfering with the aggregation of amyloid proteins may be a promising strategy for a better understanding of the mechanism of amyloidogenesis, the link to oxidative stress and make progress in finding a way to modulate the aggregation of amyloidogenic proteins.

In the current work, naked CeO2 NPs were synthesized by precipitation in the reversal microemulsions, modified with DDM, and the resulting CeO2@DDM NPs were characterized and tested for anti-amyloid and antioxidant activities. Insulin served as a model for studying the effect of nanoparticles on amyloidogenesis. The effectiveness of fabricated CeO2@DDM NPs in the formation of insulin fibrils and antioxidant activity is discussed.