Dual Modal Gene Expression and Silencing Using Viral/Nonviral Chimeric Nanoparticles for Synergistic Gene Therapy

S.K. Cho, T. Luu, S. Wong, Y.J. Kwon
UC Irvine, US

Keywords: gene delivery, viral and nonviral vectors, simultaneous expression and silencing, synergistic gene therapy


Efficient, safe, and versatile gene delivery carriers that combine the viral vectors’ high gene delivery efficiency and the nonviral vectors’ high level of flexibility for structural and functional modifications were prepared. Adeno-associated virus (AAV) was shelled with an acid-degradable polyketal (PK) layer. The PK shell was designed to 1) protect the AAV core from immune recognition, 2) assist the intracellular trafficking of the AAV core, and 3) encapsulate siRNA for simultaneous gene expression of a transgene and silencing of abnormal gene. The ChNPs showed significantly enhanced transduction, compared with unmodified free AAVs even at a low virus titer, while simultaneously silencing a target gene, which was not affected by AAV-neutralizing antibodies. Confocal microscopy studies revealed facilitated transnuclear localization of the AAV core and efficiently released siRNA from the PK shell. Furthermore, tethering the surface of ChNPs with sialic acids enabled targeted delivery of the ChNPs to CD22-expressing B cells. Simultaneously recovering the pro-apoptotic gene expression and silencing the expression of the pro-survival gene is a promising approach to synergistic cancer gene therapy. Efficiently induced apoptosis of leukemia cells by the ChNPs with the pro-apoptotic Bim-encoding AAV core and the pro-survival MCL-1 siRNA-encapsulating PK shell will also be presented.