Cytokine Response to Nanoparticles Bearing Nucleic Acid Cargo

Non-viral gene delivery systems have proved to be promising for treatment of various cancers and other diseases. They are actively explored in clinical setting to deliver a range of nucleic acids to undertake diverse therapeutic actions, including the expression of therapeutic proteins using plasmid DNA, thereby restoring the defective protein, or to knockdown aberrant proteins using RNA interference (RNAi) with short interfering RNA (siRNA). The success of such delivery systems depends on various factors such as their cationic charge affecting the binding and complexation with the nucleic acids, their ability to protect against nuclease degradation, the uptake efficiency and the localized delivery inside the cell, the intracellular dissociation ability, and the properties to escape endosomal compartment. Most importantly, the ability to remain ‘stealth’ without causing any adverse reactions in a biological system is paramount irrespective of specific application. The cytokine response to the applied therapeutic agent is a critical component in determining the success of intervention. In this chapter, we will summarize the most recent literature on cytokine response to nanoparticulate delivery systems for nucleic acids, emphasizing the factors responsible for cytokine response. Structure–function studies will be emphasized and the implication(s) of cytokine response will be discussed in the context of specific applications. Representative medical conditions where the nanoparticles are used to control the cytokine profiles will be particularly probed in pursuit of new interventions related to inflammatory disorders. It is the goal of this chapter to familiarize the reader with issues related to cytokine elicitation of non-viral nanoparticles as well as intervention strategies to address cytokine-mediated disorders.