Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection

Xin Ye, Richard Holland, Mark Wood, Chris Pasetka, Lorne Palmer, Eleni Samaridou, Kevin McClintock, Viktoriya Borisevich, Thomas W. Geisbert, Robert W. Cross, James Heyes

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)269-281
Number of pages13
JournalMolecular Therapy
Issue number1
StatePublished - Jan 4 2023


  • GalNAc
  • Marburg virus
  • conjugate
  • endosome release
  • hemorrhagic fever
  • mannose
  • siRNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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