ROS-Sensitive Cross-Linked Polyethylenimine for Red-Light-Activated siRNA Therapy

The extremely inefficient endosomal escape and intracellular release are the central barriers for effective nanocarrier-mediated RNA interference (RNAi) therapeutics. Accelerating endosomal escape and triggering intracellular release with red or near-infrared light are of particular interest due to its spatiotemporal controllability, great tissue penetration, and minimal phototoxicity. As a proof-of-concept, we explored an innovative siRNA delivery system, ^TKPEI-Ce6, that is prepared by the linking reaction of branched polyethylenimine, a reactive oxygen species (ROS)-labile crosslinker, poly(ethylene glycol), and chlorin e6 (Ce6). ^TKPEI-Ce6 efficiently condensed siRNA to form the nanoscale complex ^TKPEI-Ce6/siRNA. Under red-light irradiation (660 nm), the conjugated Ce6 produced ROS, which could accelerate endosomal escape by the destruction of the endosomal membranes and then trigger the cytosolic release of siRNA by cleaving the thioketal linker and further disrupting the nanostructure of the ^TKPEI-Ce6/siRNA. Therefore, the superior silencing efficiency of siRNA was collectively realized toward an anticancer therapy. This concept also provides new avenues for light-controlled site-specific downregulation of targeted gene expression in vivo, facilitating precise treatment of numerous diseases.