Protection from malaria infection using liver-targeted siRNA

Malaria-causing <i>Plasmodium</i> parasites infect the liver and undergo obligate and asymptomatic replication in hepatocytes prior to infection of the blood. As such, preventing liver infection will prevent blood infection, thereby prevent malaria disease, and the spread of parasites by mosquitoes. The tetraspanin CD81 is expressed on the hepatocyte plasma membrane and is a critical entry receptor for sporozoites of the major human parasite <i>Plasmodium falciparum.</i> Yet, the importance of this molecule has not been effectively exploited for malaria prevention. RNA interference (RNAi) is a clinically proven technology for the silencing of human disease-related genes and may thus represent a promising avenue for malaria prevention. Here, we report the application of CD81-targeted, N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) to efficiently silence both mouse and human hepatic CD81 <i>in vivo</i>. Using a mouse model of malaria, we show that CD81 GalNAc-siRNA blocked parasite liver infection in a dose-dependent manner and prevented the onset of blood stage infection. We further provide evidence that this approach reduced <i>P. falciparum</i> infection using human liver-chimeric mice. The data suggest siRNA as a promising host-based approach to prevent malaria infection.