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.