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

Nat Biotechnol. 2005 Jun;23(6):709-17. doi: 10.1038/nbt1101. Epub 2005 May 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / chemistry
  • COS Cells
  • Drug Delivery Systems*
  • HIV-1
  • Humans
  • Interferons / metabolism
  • Melanoma, Experimental / therapy
  • Mice
  • RNA, Small Interfering / administration & dosage*
  • Receptors, Cell Surface / physiology*
  • Receptors, HIV / physiology
  • Recombinant Fusion Proteins


  • Antibodies
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, HIV
  • Recombinant Fusion Proteins
  • Interferons