**9. Lung toxicity**

Espescially, when regarding the lung as target organ the activation of the inflammosome should be avoided. Lung targeting could in general be achieved by systemic delivery or pulmonary delivery. Pulmonary delivery enhances siRNA retention in the lungs, lowers the dose of siRNA required for efficient delivery, and therefore implicates reduced systemic toxic effects, and due to lower nuclease activity in the lung siRNA stability is increased. RNAi can be used to treat or prevent diseases affecting the lungs, such as lung cancer (Li and Huang, 2006; Tong, 2006; Jere *et al.*, 2008; Ren *et al.*, 2009; Zamora-Avila *et al.*, 2009), various types of respiratory infectious diseases (Ge *et al.*, 2004; Fulton *et al.*, 2009; DeVincenzo *et al.*, 2010), airway inflammatory diseases (Lee and Chiang, 2008; Seguin and Ferrari, 2009), and cystic fibrosis (Pison *et al.*, 2006).

Beyerle and co-workers investigated the effects of PEGylation on cytotoxicity and cellcompatibility of different PEG-PEI copolymers in murine lung cell lines and found a clear structure-function relationship (Fig. 1).

The higher the degree of PEGylation on PEI25kDa with low molecular weight PEG, the stronger was the reduction of cytotoxicity and oxidative stress, but the proinflammatory potential of PEI remained high (Beyerle *et al.*, 2010b). The same group evaluated the pulmonary toxicity of PEI/siRNA complexes and found at day three after intratracheal delivery still high numbers of neutrophils and high levels of proinflammatory cytokines in the airspace of polyplex treated mice (Beyerle *et al*., 2011a and Beyerle *et al*., 2011c). The higher inflammatory potential but lower toxicity of PEI modifications is still an issue to be overcome when targeting pulmonary diseases. There is an urgent need to balance the efficacy and toxicity of such nucleic acid carriers.
