Dual functional RNA nanoparticles containing phi29 motor pRNA and anti-gp120 aptamer for cell-type specific delivery and HIV-1 inhibition.
The potent ability of small interfering RNA (siRNA) to inhibit the expression of complementary RNA transcripts is being exploited as a new class of therapeutics for diseases including HIV. However, efficient delivery of siRNAs remains a key obstacle to successful application. A targeted intracellular delivery approach for siRNAs to specific cell types is highly desirable. HIV-1 infection is initiated by the interactions between viral glycoprotein gp120 and cell surface receptor CD4, leading to fusion of the viral membrane with the target cell membrane. Once HIV infects a cell it produces gp120 which is displayed at the cell surface. We previously described a novel dual inhibitory anti-gp120 aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities. We also demonstrated that gp120 can be used for aptamer mediated delivery of anti-HIV siRNAs. Here we report the design, construction and evaluation of chimerical RNA nanoparticles containing a HIV gp120-binding aptamer escorted by the pRNA of bacteriophage phi29 DNA-packaging motor. We demonstrate that pRNA-aptamer chimeras specifically bind to and are internalized into cells expressing HIV gp120. Moreover, the pRNA-aptamer chimeras alone also provide HIV inhibitory function by blocking viral infectivity. The Ab' pRNA-siRNA chimera with 2'-F modified pyrimidines in the sense strand not only improved the RNA stability in serum, but also was functionally processed by Dicer, resulting in specific target gene silencing. Therefore, this dual functional pRNA-aptamer not only represents a potential HIV-1 inhibitor, but also provides a cell-type specific siRNA delivery vehicle, showing promise for systemic anti-HIV therapy.
Division of Molecular and Cellular Biology, City of Hope, Duarte, CA, USA. Jzhou@coh.org
Jiehua
J
Zhou
Yi
Y
Shu
Peixuan
P
Guo
David D
DD
Smith
John J
JJ
Rossi
D000818:Animals; D052157:Aptamers, Nucleotide / Q000235:genetics* / Q000378:metabolism; D017103:Bacillus Phages / Q000235:genetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D019302:HIV Envelope Protein gp160 / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D053758:Nanoparticles; D034622:RNA Interference; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism
D052157:Aptamers, Nucleotide; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D034741:RNA, Small Interfering; D012367:RNA, Viral; D043244:Ribonuclease III
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