Intelligent nucleic acid delivery systems based on stimuli-responsive polymers

Despite significant advances in the past two decades, gene therapy is still in the stage of clinical trials worldwide mainly due to the lack of safe and efficient delivery vehicles for therapeutic nucleic acids. Among the various attempts to develop clinically applicable gene therapy, polymer-based nucleic acid delivery systems have attracted great interest, especially for the exciting RNAi-based gene therapy. Regarding in vivo nucleic acid delivery, in particular via intravenous injection, there are many extraand intracellular obstacles, some of which are conflicting. Virus-mimicking nucleic acid delivery systems that combine multiple and programmable functions are thought to be very promising for conquering these challenging barriers. In this review article, we highlight recent progress in stimuli-responsive polymers that have been applied in fabrication of non-viral multi-functional nucleic acid vehicles, which are categorized by the type of stimulus: reduction potential, pH, temperature, and others. In each section, intelligent pDNA delivery systems are introduced first, followed by summarizing various responsive polymer-based siRNA vehicles. Considering the great potential of RNAi-based gene therapy, we devote some space to the recent progress of multi-functional siRNA delivery systems. In addition, different requirements in designing polymer-based siRNA and pDNA carriers are also specified in this review.