Virus-Inspired Mimics: Dual pH-Responsive Modular Nanoplatforms for Programmable Gene Delivery without DNA Damage with Assistance of Light.

Although tremendous efforts have been made to construct gene vectors incorporating multiple functionalities and moieties, designing gene vectors integrating innovative features to successfully negotiate biological impediments which hamper efficacious responses in gene-based therapy is still very urgent. Herein, a light-induced virus-inspired mimic in which a modular envelope was utilized to mask PEI/DNA polyplexes, was developed based on two pH-responsive polymers. The virus-inspired envelope, which was capable of achieving multi-targeting and dual pH-responsiveness in endo/lysosomal compartments, was composed of an iRGD-modified module and a NLS(Cit)-functionalized module. The envelope conjugated with chlorin e6 was shielded on the surface of PEI/DNA polyplexes. Dual pH-responsive deshielding of the virus-inspired mimic in endo/lysosomes allowed generation of a non-fatal amount of ROS under short-time photoirradiation, leading to photochemical internalization and much more substantial enhancement in light-induced gene expression without DNA damage caused by ROS. Confocal images revealed the virus-inspired mimic achieved successful nuclear translocation of chlorin e6, resulting in nucleus-targeting photodynamic therapy. Furthermore, pTRAIL-mediated gene therapy, accompanied by a fatal amount of ROS under long-time photoirradiation, additionally consolidated in vitro anti-tumor outcomes. This study demonstrates a novel paradigm of "one arrow, two hawks", accomplishing a combination of enhanced gene therapy and photodynamic therapy.