Virus-Inspired Mimics: Dual-pH-Responsive Modular Nanoplatforms for Programmable Gene Delivery without DNA Damage with the 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 polyethylenimine/DNA (PD) polyplexes, was developed based on two pH-responsive polymers. The virus-inspired envelope, which was capable of achieving multitargeting and dual-pH-responsiveness in endo/lysosomal compartments, was composed of an internalizing arginylglycylaspartic acid-modified module and a citraconic anhydride-modified nuclear localized signal-functionalized module. The envelope conjugated with chlorin e6 (Ce6) was shielded on the surface of PD polyplexes. Dual-pH-responsive deshielding of the virus-inspired mimic in endo/lysosomes allowed generation of a nonfatal amount of reactive oxygen species (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 that the virus-inspired mimic achieved successful nuclear translocation of Ce6, resulting in nucleus-targeting photodynamic therapy (PDT). Furthermore, pTRAIL-mediated gene therapy, accompanied by a fatal amount of ROS under long-time photoirradiation, additionally consolidated in vitro antitumor outcomes. This study demonstrates a novel paradigm of "one arrow, two hawks," accomplishing a combination of enhanced gene therapy and PDT.