# Nanotechnology Solutions for Controlled Cytokine Delivery: An Applied Perspective
## 3 Nanoparticles as Cytokine Delivery Systems
### Types of Nanoparticles for Cytokine Delivery  
#### 3.1.1 Polymeric Nanoparticles  
Polymeric carriers represent one of the best studied delivery vehicles, ranging from gels to nanoparticles, and have been used to improve circulation times, stability, and the capacity to encapsulate and supply therapeutic molecules compared to lipid formulations [45]. This type of particle often exhibits excellent biocompatibility, low toxicity and biodegradability profiles. The most commonly used polymer is polylactic-coglycolic acid (PLGA), which is a US FDA-approved polymer synthesized using the oil-in-water emulsion method [16; 45]. However, other methods such as spray-drying, salting out and nanoprecipitation can be employed to produce these nanoparticles and it is important to consider that the chosen method will influence their properties, such as size and surface [44]. Other important characteristics of these nanocarriers include: high stability, easy encapsulation or adsorption of both hydrophobic and hydrophilic molecules [46], facile surface and structure modification allowing the design of multifunctional engineered delivery systems [44]. [PERSON] and co-workers reported the development of PLGA polyethylene glycol (PEG) nanoparticles encapsulating IL-10 to prevent plaque formation in advanced atherosclerosis lesions, and argued that the encapsulated cytokine may have a longer circulation life compared to its adsorption to the nanoparticle [39]. The PLGA polymer was charged at terminal portions for more effective electrostatic interactions with IL-10, and PEG was used to functionalize the nanoparticle, allowing a greater nanoparticle stability and prolonged \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Type** & **Functionalization** & **Application** & **Delivered** & **Experimental** & **Models** & **References** \\ \hline \multirow{6}{*}{Polymeric NPs} & \multirow{3}{*}{PLGA-PEG} & Plaque inhibition in atherosclerosis & IL-10 & Mice & [39] \\ \cline{3-6}  & & Anti-inflammatory activity in reperfusion injury & & anti-IL6 antibody & Dendritic cell line; & [40] \\ \cline{2-6}  & & & & Mice & & \\ \cline{2-6}  & & & & & & \\ \cline{2-6}  & & & & & & \\ \cline{2-6}  & & & & & & \\ \hline \multirow{2}{*}{Polymeric NPs} & \multirow{2}{*}{PLGA-NG2} & Plaque scleroosis therapy & ILF & Oligodendrocyte precursor cell line; & [33] \\  & & & & & Mice & \\ \cline{2-6}  & PEG-CD11b-PLA & Neurotogeneration and anti-inflammatory activity & & ILF & Macrophage cell line & [32] \\ \cline{2-6}  & & & & & & \\ \cline{2-6}  & & & & & & \\ \cline{2-6}  & & & & & & \\ \hline \multirow{2}{*}{CISO/H} & \multirow{2}{*}{Tissue regeneration} & VEGF; stromal cell derived factor-1\(\alpha\) & Mice & [15] \\ \cline{2-6}  & & w/o functionalization & Melanoma vaccination & INF-\(\gamma\) & Mice & [38] \\ \cline{2-6}  & PEG-liposome & Cancer therapy & IL-2 and anti-CD137 & Mice & [42] \\ \hline Gold NPs & NGR & Cancer therapy & TNF & Mice & [34] \\ \hline Silica NPs & \multirow{2}{*}{w/o functionalization} & \multirow{2}{*}{Immunomodulation} & IL-4 & Macrophage cell line; & [35] \\ \cline{2-6}  & & & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Nanoparticle-based systems for the delivery of cytokines and applications in biomedicine. systemic circulation by immune shielding [39; 47]. In addition, the researchers proved that neither the IL-10-containing nanoparticles nor the empty ones caused any in vitro or in vivo toxicity [39]. [PERSON] and co-workers developed nanoparticles containing chitosan, a well-studied polysaccharide polymer commonly used due to its biocompatibility and biodegradability properties [15], encapsulating IL-10 conjugated with iron oxide nanoparticles for magnetic resonance imaging (MRI) ability, without affecting the mechanical and targeting properties of the nanoparticles. The authors demonstrated that these nanocarriers had easy and efficient loading, and controlled release, effectively targeting plaques in atherosclerotic mice [41; 48].