Serum-resistant, reactive oxygen species (ROS)-potentiated gene delivery in cancer cells mediated by fluorinated, diselenide-crosslinked polyplexes

The transfection performance of polycations is often hampered by various systemic barriers that pose conflicting requirements for material design. Herein, we developed fluorinated, ROS-cleavable polyethylenimine (PEI) for effective and serum-resistant gene delivery to cancer cells, by harmonizing the inconsistency between DNA condensation and release, and the inconsistency between cellular internalization and serum stability. Low-molecular weight (MW) PEI was cross-linked with a diselenide-containing linker and further modified with fluorocarbon chains. The obtained high-MW DSe-PEI-F has potent DNA condensation as well as intracellular DNA delivery capabilities, while in the cytoplasm of cancer cells, it can rapidly degrade into low-MW segments upon ROS treatment to promote DNA release and reduce the material toxicity. As such, DSe-PEI-F showed high transfection efficiencies in cancer cells in the presence of serum, outperforming the commercial reagent PEI 25k by several orders of magnitude. This study thus provides an effective approach to overcome various barriers against non-viral gene delivery, which contributes to the development of a new class of gene vectors with high efficiency and low toxicity.