# Nanotechnology Solutions for Controlled Cytokine Delivery: An Applied Perspective
## 3 Nanoparticles as Cytokine Delivery Systems
### The Specific Case of the IL-6 Cytokine Family  
Occasionally, unregulated cytokine production can result in unwanted conditions of inflammation, a common situation in organ transplants. In such cases, immunosuppressive therapies using immunoregulatory molecules are a viable option. [PERSON] and co-workers developed a controlled formulation composed of nanoparticles made of PLGA-PEG and loaded with anti-IL-6 antibody for the targeting of IL-6-mediated inflammatory responses (Figure 2a) [40]. For that, the authors perfused a heart with nanoparticles to deliver anti-IL-6 antibody prior to transplantation, in order to suppress chronic rejection. In addition, the direct delivery of these nanoparticles prevented systemic immunosuppression and allowed the use of reduced anti-IL-6 doses (more than 200 times when compared to the systemic administration) with positive results and minimal side effects [40]. Another study using LIF-loaded PLGA nanoparticles was carried out by [PERSON] and co-workers [33]. LIF is a pleiotropic cytokine of the IL-6 family which can act in diverse organs and play several functions in health and disease, depending on the cell type and environment [63]. The objective of the study was to develop a biodegradable and biocompatible nanocarri capable of maintaining load stability and a controlled cytokine release for a prolonged therapeutic effect, verified over several days. The produced nanoparticles were tested for the delivery of pro-remyelinating factors (LIF) to the central nervous system as a therapeutic strategy for multiple sclerosis disease (Figure 2b). LIF has been proven to promote remyelination and tissue repair [64; 65], avoiding off-target effects by nanoparticle functionalization with anti-NG2 chondro sulphate proteoglycan antibodies. This functionalization demonstrated to be effective for the targeted delivery of LIF to oligodendrocyte precursor cells, promoting their differentiation to repair myelin, and avoiding a systemic exposure to the cytokine. Moreover, the potency of the targeted drug delivery system was high, requiring minimal doses of LIF (picomolar range) to increase demyelination, in vivo, using a mouse model [33]. The pleiotropic activity of LIF was shown in a study by [PERSON] and co-workers, in which the authors demonstrated that LIF decreases neural cell degeneration in vitro and in vivo (Figure 2c) [66]. However, LIF-dependent neuroprotection is influenced by the short half-life and bioactivity of the cytokine in blood [32]. Thus, the authors developed LIF-loaded nanoparticles made of PEG-poly(lactic acid) (PLA) to deliver and prolong the stability and activity of the cytokine for in vivo applications [32]. The PEG-PLA LIF-loaded nanoparticles, termed as NanoLIF, demonstrated a gradual release of LIF in  
Figure 2: Biotechnological approaches using nanoparticles and cytokines from IL-6 family. **(a)** PLGA (polylactic-coglycolic acid)–PEG (polyethylene glycol) nanoparticles encapsulating anti-IL-6 antibodies for regulation of the inflammatory response in heart transplantation in mice. **(b)** PLGA–anti-NG2 chondro antibody particles encapsulating LIF for remyelination of the central nervous system as a therapeutic strategy for multiple sclerosis disease. **(c)** PLA (poly(lactic acid))–anti CD11b antibody particles encapsulating LIF and providing neuroprotective and anti-inflammatory effects to damaged brain sites. in vitro tests, which enhances the therapeutic efficacy for future in vivo applications, and an increase in LIF half-life (30 h) in comparison to other nanomaterials (2 h) [67]. The NanoLIF system also demonstrated high loading capacity (up to 331 ng/mL LIF) and the ability to protect the cytokine from thermal degradation. Additionally, the authors also devised a strategy for the target delivery of LIF to inflammatory macrophages through surface functionalization of NanoLIF with CD11b antibody (CD11b-NanoLIF), that can bind to the CD11b membrane protein overexpressed on macrophages [32].