**3.1 General synthesis protocol**

The most common method announced for the synthesis of CD based polymers, is characterized by employing a suitable solvent which could be either organic solvent or, in specific cases water, for the dissolution of the CDs. Afterwards, under continuous stirring, the chosen linking agent is added to the solution. Nevertheless, when required, the introduction of a catalyst occurs before the linking agent, and in specific cases, an increase in temperature is necessary to start the cross-linking reactions. The use of an ultrasound bath instead of stirring was also considered [35]. Eventually, either a sol–gel process or a precipitation polymerization can be observed, leading to the formation of a monolithic block or a precipitate, respectively. Also, in those cases in which the cross-linker is in the liquid form, and able to solubilize the CD, a melt polymerization can be performed [36, 37].

Once the synthesis is completed, the solvent, the catalyst, eventual unreacted monomers, and by-products are removed from the synthesized product by purification with water or other volatile solvents. In the end, a dry solid powder is collected [37–39]. Another well-known approach to synthesize CD-NSs is achieved through simple dehydration reactions. In this case, the CDs and the cross-linker, which is usually an acid bearing two or more carboxylic groups, are solubilized in water. After the addition of a suitable catalyst, the solution is heated to remove the water introduced as solvent as well as the water released as a by-product of the crosslinking condensation reaction. Moreover, the use of vacuum together with the temperature allows to shift the equilibrium of the reaction toward the products [40, 41]. Besides, less used synthetic routes report the use of interfacial or radical polymerization. In the first case, two immiscible phases such as a water solution of CD and a chlorinated solvent solution containing the chosen cross-linker, are mixed and stirred vigorously. The cross-linking occurs rapidly at the interface of the immiscible phases, and a precipitate is obtained [39]. While in the second case, a multistep procedure involving also preliminary derivatization of CD was displayed [42].

#### **3.2 General classification**

In general, based on the technological evolution of these materials, CD-NSs can be classified into four generations, considering their chemical composition and properties [19]. The first generation comprises all those NSs synthesized by a simple one-step reaction of CDs with a cross-linker. This generation was further divided into sub-categories according to the chemical nature of the linking molecules adopted for the synthesis. In this frame, carbonate, ester, ether, and urethane types are the most reported. These specific types of NSs will be described in more detail in the following paragraphs. Subsequently, the introduction of specific functions such as charge or luminescence to the final polymer structure defined the second generation of NSs. These materials displayed more complex polymer architectures achieved either via pre- or post-synthesis functionalization. In the first case, the introduced functions were limited to the surface of the polymer, whereas in the second case a more homogeneous distribution was observed. Referring to the division into generations, the 3rd generation deals with stimuli-responsive NSs, able to modulate their behavior (for example increasing/decreasing a drug release) according to the external environment.

#### *3.2.1 CD-based polyurethane NSs*

Urethane, or carbamate, CD-NSs are synthesized by reacting CDs (or a different dextrin) with a suitable diisocyanate as, for example, hexamethylene diisocyanate (HDI), toluene–2,4-diisocyanate (TDI). The reaction scheme is reported below

(**Figure 1**, inset a). The resulting NSs are usually characterized by a rigid structure and a negligible swelling in water (in comparison with other CD-NSs), and organic solvent and high resistance to chemical degradation. Carbamate CD-NSs, were originally developed by Li and Ma for the treatment of wastewaters, as an alternative for activated carbon. They demonstrated with NSs remarkable performances in the removal of organic molecules such as p-nitrophenol reducing concentration of waste from 10−7–10−9 M to ppt level. The surface area was usually lower than activated carbon, (1–2 m2 /g, two orders of magnitude) but it is supposed that organic molecules can be adsorbed, diffuse through the surface, and be absorbed inside the bulk of NSs [43].

The good affinity of organic molecules showed for pollutants [44], is also demonstrated by the application of urethane NSs in the complexation with biologically relevant compounds, such as bilirubin or amino acids. In 2006, Tang et al. evaluated the difference in absorption of aromatic amino acids and branched-chain amino acids: the absorption of branched-chain amino acids was negligible whereas NSs absorbed 24% of the aromatic amino acids.

In previous works the same polymer was tested for the absorption of bilirubin, reducing the initial concentration of bilirubin (40 mg/l) up to 92.6% after the addition of the NS [45].
