Intracellularly Disintegratable Polysulfoniums for Efficient Gene Delivery

Abstract

Amine‐based cationic polymers have been extensively explored as nonviral carriers for gene delivery, but inefficient intracellular unpacking of polymer/DNA complexes (polyplexes) to release plasmids is still a key limiting step to high transfection efficiency. Furthermore, the amine‐resulting cationic charges in the polymer chains, and even their degraded fragments, inherently interfere with transgene expression. A cationic polymer capable of converting to uncharged fragments once inside cells would not only quickly release the DNA, but also not interfere with the gene transcription process for efficient gene expression and low toxicity. A new class of polysulfoniums that can degrade into neutral thioether fragments triggered by reactive oxygen species (ROS) is reported. The polysulfoniums condense DNA into nanosized polyplexes, which can be quickly internalized and efficiently escape from endo/lysosomes. In cancer cells, the oxidation of the boronic acid/ester by the elevated ROS levels triggers polysulfonium to break down into neutral thioether fragments, efficiently releasing DNA for gene expression. More importantly, the polyplexes have excellent serum resistance; in vivo, they efficiently deliver the suicide gene pTRAIL to intraperitoneal tumors eliciting effective anticancer activity.