# Nanotechnology Solutions for Controlled Cytokine Delivery: An Applied Perspective
## 1 Introduction  
Cytokines are a group of small proteins with a molecular weight of less than 30 kDa, used by cells as mediators for cell-cell interactions, with an important role in cell signaling. They regulate a wide range of biological functions for the maintenance of normal host physiology, such as inflammation, repair, proliferation and differentiation, among several others [1, 2]. In addition, the multifunctional activity of these proteins depends on the context of the specific tissue/organ and cytokine environment; it is concentration-dependent, being often designated as pleiotropic, as one cytokine can display different functions [2]. For instance, Oncostatin M (OSM), which belongs to the IL-6 family of proteins, can be involved in impaired healing in chronically inflamed wounds, but is proved to stimulate mitogenic responses of dermal fibroblasts and restore the extracellular matrix, important features for skin repair [3]. Nowadays, around 200 cytokines have been identified and studied, with the vast majority belonging to the four-\(\alpha\)-helix bundle family [4]. They can be classified into pro- or anti-inflammatory cytokines, growth factors, lymphokines or chemokines [5]. In addition to the cytokines being grouped into different families according to their structure and specificity, their respective receptor complex composition is also important for classification [6]. These small proteins exert their function through binding to specificreceptors present on the membrane of target cells. They are usually composed of one polypeptide chain (the cytokine specific \(\alpha\) subunit) and a signal-transducing \(\beta\) subunit [4]. Cytokines are involved in many diseases and redundancy is another well-known hallmark, as multiple cytokines can mediate similar functions [7]. For instance, the inflammatory cytokines TNF-\(\alpha\), IL-1 or IL-6 modulate myocardial function and promote the progression of heart failure [8]. Furthermore, IL-4 and IL-10 play an important role in pregnancy and a deficiency in these cytokines contributes to infertility or hypertensive disorders [7]. TNF-\(\alpha\) and IL-4, -5, -13 are involved in the inflammatory process of bronchial asthma disease [9]. In chronic kidney disease, the up-regulation of pro-inflammatory cytokines, such as IL-1, -6 and IFN-\(\gamma\), is responsible for the activation of leucocytes resulting in apoptosis of nephrons [10]. Cytokines are also biomarkers of HIV infection, since the production of IL-1, -6, -4, -10, or TNF-\(\alpha\) is increased in infected patients, stimulating HIV replication [11]. The presence of an abnormal production of cytokines (IL-1\(\alpha\) and IL-1\(\beta\)) was also observed in Alzheimer's disease, the most common form of dementia [12]. Even in cancer, the presence and concentration of cytokines influence cancer cell proliferation. IL-1\(\beta\) and IL-8 promote angiogenesis and growth of different cancer cells [13]. The use of several cytokines as therapeutic targets is currently approved by FDA [4]. Although cytokines may be suitable biomarkers for health and disease, and their exploitation as therapeutic agents has been greatly expanded, the rapid clearance by proteases and excretion mechanisms once in vivo still limit their application [14,15]. In fact, it is necessary to improve half-life and protein stability. The relatively large size of cytokines or growth factors as well as their potential toxicity at high doses suggest that safe, specific and controlled delivery techniques are required in clinical administration [16]. Nanotechnology, currently employed in therapeutics, diagnostics and imaging [17], has been widely used to overcome many of these limitations. Nowadays, there are many nano-based drug delivery systems applied in nanomedicine, from nanoparticles to nanogels, nanotubes, or nanochips; however, the first remain the most widely used [16,18].