Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors

Erwei Song, Pengcheng Zhu, Sang Kyung Lee, Dipanjan Chowdhury, Steven Kussman, Derek M. Dykxhoorn, Yi Feng, Deborah Palliser, David B. Weiner, Premlata Shankar, Wayne A. Marasco, Judy Lieberman

Research output: Contribution to journalArticle

817 Scopus citations

Abstract

Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.

Original languageEnglish (US)
Pages (from-to)709-717
Number of pages9
JournalNature biotechnology
Volume23
Issue number6
DOIs
StatePublished - Dec 9 2005

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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    Song, E., Zhu, P., Lee, S. K., Chowdhury, D., Kussman, S., Dykxhoorn, D. M., Feng, Y., Palliser, D., Weiner, D. B., Shankar, P., Marasco, W. A., & Lieberman, J. (2005). Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nature biotechnology, 23(6), 709-717. https://doi.org/10.1038/nbt1101