Chemical modifications to the siRNA backbone decrease in vivo induction of serum inflammatory cytokines and antiviral responses. Mice were injected twice IV with lyophilized 98N12-5(1) siRNA nanoparticles at 2 mg/kg siRNA before (a) blood collection by cardiac puncture or (b) infection with 12,000 PFU PR8 virus. (a) Serum IFN-α concentration was determined by ELISA. (b) Lung viral RNA level was determined by branched DNA assay and normalized to GAPDH mRNA levels. Data from individual mice shown; black lines indicate mean for each group. *P < 0.05 compared to PBS group by 7-group one-way ANOVA followed by Bonferroni's multiple comparison test. ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IFN, interferon; IV, intravenous; PBS, phosphate-buffered saline; PFU, plaque-forming unit; siRNA, short-interfering RNA.