Intravenous Administration of Antisense Oligonucleotide Incorporated into PLGA Nanoparticles Alters the Pattern of Organ Distribution and Gene Knockdown Effects

Antisense oligonucleotides (ASOs) were recently approved for treating diseases that are unable to be treated by conventional modalities. However, the approved ASOs target limited organs, particularly the liver, as a result of their pharmacokinetic nature. Here, we report a detailed analysis of the biodistribution and gene knockdown (KD) activity of ASO in organs in the whole body by using ASO incorporated into nanoparticles (NPs). Biodegradable poly(lactide-<i>co</i>-glycolic acid) was used as a matrix of NPs and the <i>Malat1</i> gene, which is expressed in many organs, was selected as a target of ASO. NPs enabled dramatically high accumulation of ASO in the liver, spleen, lung, and heart compared with that of naked ASO in mice. Notably, high accumulation in the organ did not always result in the KD effect because of the difference of susceptibility to the KD effect in cells that take up NPs. While we used 1 order of magnitude lower dose of ASO compared with conventional naked ASO treatments, NPs showed KD effects not only in the heart but also in the lung and kidney, where naked ASO did not show KD effects. Here, we clarify the unique biodistribution and KD effects of ASO incorporated in NPs. These findings will contribute to the development of an ASO delivery system to target atypical organs with reduced side effects.