Image: Illustration of VIPER-induced endo/lysosomal escape. At neutral pH, VIPER self-assembles into nanoparticles with melittin restricted to the pH-sensitive domain. After endocytosis by cells, the acidic endo/lysosome environment induces the hydrophilic phase transition of pDIPAMA, enabling melittin exposure, disruption of the endo/lysosomal membrane, and endo/lysosomal escape.
Clinical translation of nucleic acids drugs has been stunted by limited delivery options. Herein, we report a synthetic polymer designed to mimic viral mechanisms of delivery called VIPER (virus-inspired polymer for endosomal release). VIPER is composed of a polycation block for condensation of nucleic acids, and a pH-sensitive block for acid-triggered display of a lytic peptide to promote trafficking to the cell cytosol. VIPER shows superior efficiencies compared to commercial agents when delivering genes to multiple immortalized cell lines. Importantly, in murine models, VIPER facilitates effective gene transfer to solid tumors.