Dual modal gene expression and silencing using viral/nonviral chimeric nanoparticles for synergistic gene therapy

摘要

Combining the advantages of virus (e.g., high transduction) with that of nonviral materials (e.g., low immunogenicity) is considered to be a logical approach to develop ideal gene delivery vector. In this context, adeno-associated virus (AAV) was shelled with an acid-degradable polyketal (PK) layer to produce viral/nonviral chimeric nanoparticles (ChNPs). ChNPs showed significantly enhanced transductioh of human lymphoma B cells, compared with unmodified free AAVs even at low virus titer, while simultaneously silencing a target gene. As hypothesized, the gene delivery efficiency of the ChNPs was not affected by AAV-neutralizing antibodies. Confocal microscopy studies revealed facilitated nuclear translocation of the AAV core and efficient release of siRNA from the PK shell into the cytoplasm. Furthermore, ChNPs with pro-apoptotic AAV (Bim) core and pro-survival siRNA (MCL1) shell induced synergistic apoptosis in leukemia cells.