MicroRNAs (miRNAs) are single-stranded noncoding RNAs ∼21-nucleotide (nt) in length and regulate gene expression at the posttranscriptional level. miRNAs are involved in almost every area of biology, including developmental processes, disease pathogenesis, and host-pathogen interactions. Dysregulation of miRNAs in various disease states makes them potential targets for therapeutic intervention. Specific miRNAs can be silenced by anti-microRNAs (anti-miRs) that are chemically modified antisense oligonucleotides complementary to mature miRNA sequences. In vivo delivery of anti-miRs is the main barrier in achieving efficient silencing of target miRNAs. A new systemic delivery agent, interfering nanoparticles (iNOPs), was designed and prepared from lipid-functionalized poly-L-lysine dendrimer. iNOPs can efficiently deliver small RNAs, including short interfering RNAs, miRNA mimics, and anti-miRs. Systemic delivery of a chemically stabilized anti-miR-122 by iNOPs effectively silences miR-122 in mouse liver. Intravenous administration of 2 mg/kg anti-miR-122 complexed with iNOP-7 results in 83% specific silencing of target miRNA. The specific silencing of miR-122 by iNOP-7 is long lasting and does not induce an immune response.