# Nanotechnology Solutions for Controlled Cytokine Delivery: An Applied Perspective
## 2 II-6 Cytokine Family  
Composed of interleukins (IL)-6, -11, -27, -31, cardiotrophin-1 (CT-1), cardiotrophin-like cytokine factor 1, ciliary neurotrophic protein factor (CNTF), leukemia inhibitory factor (LIF) and oncostatin M (OSM), the IL-6 cytokine family comprises multifaceted cytokines [19]. The members of this family exert effects at the level of different organs such as skin, pancreas, liver, lung, reproductive system,brain, bone metabolism and inflammation, with impact on cancer and other disorders, playing both pro- or anti-inflammatory roles (reviewed in [20; 21]).  
These cytokines comprise four long \(\alpha\)-helices arranged to form an up-up-down-down topology (Figure 1a), thus forming a subfamily of the helix bundle cytokines [22]. The main characteristic responsible for grouping these cytokines in the same family is the existence of a common signaling receptor subunit glycoprotein 130 kDa (gp130), present in the membrane of many cell types [23]. Recently, two other interleukins have been added to this family, IL-35 and IL-39, due to this shared common feature [24; 25]. The cytokine receptor is also composed of another polypeptide chain, the cytokine specific subunit, which is also important for intracellular signaling [26]. Different cytokines from this family can share the same receptors or use more than one receptor to perform signaling (Figure 1b). However, there are also \(\alpha\) subunits in the free soluble form, able to form cytokine/receptor complexes and posteriorly bind to the membrane-bound gp130, a process designated as trans-signaling. Additionally, free soluble gp130 is also considered an inhibitor of IL-6 trans-signaling since it can bind to cytokine/receptor complexes outside the membrane, thus preventing intracellular signaling [27]. Subsequently to the binding event, the cell surface receptor complex activates different pathways such as the JAK/STAT, RAS/MAPK or PI3K signaling pathways [28], leading to various pathological and physiological functions which depend on the biochemical pathways. While highly attractive for biomedical use due to their pleiotropic activity, these cytokines, when administered in vivo, are rapidly degraded [14; 15]. The use of nanomaterials to deliver these molecules provides a valid solution, acting as a protective vehicle from degradation. Although encapsulation of cytokines allows controlled and specific delivery to target cells, the nanomaterials must be able to release the molecules, as in most cases, cytokines needs to bind the membrane receptor for its activity to occur. An alternative approach is to link the cytokine to the surface of the nanomaterial. However, the potential ligation to free soluble gp130 is problematic and can hinder effective cytokine delivery. Similarly, nanogram levels of delivered TNF \(\alpha\) can bind to its soluble receptor molecules, resulting in the lower binding to the membrane receptors and inhibition of posterior intracellular signaling [29]. This drawback can be overcome by functionalizing the surface of the produced nanomaterials with protective molecules (e.g., PEG) in order to mask the cytokines until they reach the target cells.  
Although several applications of cytokines in treatments or even in diagnosis are recognized, their delivery to the sites of interest, using nanocarriers, is insufficiently explored, mainly with regard to the IL-6 family. In fact, IL-6 is still the most studied protein of this family, and it is important to transfer this knowledge to the remaining cytokines so to improve or complement the type of treatment adjusted to the disease.