## 5 Interactions of Macromolecules with Nanomaterials  
Understanding the interactions between a nanostructure and a biomolecule (proteins, lipids, and carbohydrates, among others) is relevant to the functionalization of nanomaterials. At this interface, interactions occur that depend mainly on the physicochemical characteristics of the surface of the nanostructure, in which one or several chemically reactive groups can coexist, generating chemical conjugation or adsorption mechanisms, and the latter is generally of a non-covalent type, such as hydrogen bridges, van der Waals forces, and ionic interactions [45]. In the case of milk proteins, they bind to molecules or ions with different affinities or degrees of specificity. For example, caseins \(\alpha\)s1, \(\alpha\)s2, and \(\beta\) bind calcium through their serine and phosphate residues; this mechanism is common in nature; for example, calcium phosphate nanoparticles are involved in the regulation of lactose synthesis [46]. With respect to these proteins, pH affects the formation of complexes between iron ions and caseins because hydrogen ions compete with metal ions for binding to proteins [47]. At low pH, protonation of the amino group of amino acid ions reduces the ability of proteins to bind iron, whereas at higher pH, these amino acids will be negatively charged and tend to form complexes with cations. The formation of these complexes also depends on the concentration of iron, the number of binding sites, and pH, all of which have an impact on the properties of the final product. In this case, the release of transported substances mainly depends on the pH and swelling behavior of the proteins in nano-vehicles in food technology [48]. One such widely studied protein is bovine serum albumin (BSA), since it naturally transports hydrophobic molecules such as vitamins, hormones, and other plasma constituents and also has three specific domains that favor binding with ions, lipids, and nucleotides [46; 47; 48; 49]. In the case of gold nanoparticles bound to proteins, these interactions are electrostatic, hydrophobic, or via specific binding affinity [50]. Mainly, covalent conjugation strategies have been exploited by employing a thiolate group on the nanoparticle surface or by forming bonds with the amino or carboxyl group of the protein. Nanocomplexes between proteins and polysaccharides have attracted attention because of their electrostatic interactions between two or more polyelectrolytes. This is due to the affinity of proteins to bind to bioactive compounds via hydrogen bonds and hydrophobic interactions, which increases encapsulation efficiency, while polysaccharides are a protective barrier to prevent the degradation of bioactive compounds under gastric conditions. The interactions in these nanostructured systems are determined mainly by the nature of the nanostructure, as well as by biomolecular and system conditions such as pH, among others. The identification of the adsorption or chemical conjugation interactions that occur in each nanostructured system must be considered, since they will influence the internalization pathways into cells and the stability or techno-functional characteristics of a product.