Hepatic, MyD88-dependent toll-like receptors are activated by in vivo application of LNP01-formulated siRNAs

Introduction: siRNAs are being developed for the therapeutic use in liver cancer, viral hepatitis, metabolic disorders and others. We have previously shown that chemical modifications of siRNAs may suppress immunologically mediated off-target effects in isolated liver cells in vitro. Here, we assessed efficacy and the Toll-like receptor dependent immune-stimulatory effects of differently modified siRNAs in vivo. Methods: Nanolipid-formulated (LNP01) siRNAs, preferentially targeting the liver, were injected into C57Bl/6, TLR3-/- and MyD88-/- mice. After different time points (6h, 24h, 48h, 72h and 96h) different…