Marburg virus (MARV)
infection results in severe
viral hemorrhagic fever with mortalities up to 90%, and there is a pressing need for effective
therapies. Here, we established a
small interfering RNA (
siRNA) conjugate platform that enabled successful subcutaneous delivery of siRNAs targeting the MARV
nucleoprotein. We identified a hexavalent
mannose ligand with high affinity to macrophages and dendritic cells, which are key cellular targets of MARV
infection. This
ligand enabled successful
siRNA conjugate delivery to macrophages both in vitro and in vivo. The delivered hexa-
mannose-
siRNA conjugates rendered substantial target gene silencing in macrophages when supported by a
mannose functionalized endosome release
polymer. This hexa-
mannose-
siRNA conjugate was further evaluated alongside our hepatocyte-targeting GalNAc-
siRNA conjugate, to expand targeting of infected liver cells. In MARV-Angola-infected guinea pigs, these platforms offered limited survival benefit when used as individual agents. However, in combination, they achieved up to 100% protection when dosed 24 h post
infection. This novel approach, using two different
ligands to simultaneously deliver
siRNA to multiple cell types relevant to
infection, provides a convenient subcutaneous route of administration for treating
infection by these dangerous pathogens. The
mannose conjugate platform has potential application to other diseases involving macrophages and dendritic cells.