pH-sensitive siRNA delivery systems

RNA interference is a promising therapeutic modality to treat human diseases by specifically silencing the expression of disease-related genes. Effective gene silencing requires specific delivery of small interfering RNA (siRNA) into target tissue and cytosolic release in target cells. The cytoplasmic membrane of endosomal-lysosomal compartments is the final barrier for effective cytosolic siRNA delivery. pH-sensitive siRNA delivery systems have been designed to overcome this barrier and to facilitate cytosolic siRNA release utilizing the pH difference between plasma and endosomal-lysosomal compartments. The pH-sensitive delivery systems have a common feature of using materials with pH-sensitive amphiphilicity. The pH-sensitive materials, both lipids and polymers, become more amphiphilic at decreased pH in endosomes and destabilize the cytosolic membrane to facilitate cytosolic siRNA release. Significant progress has been made on the design and development of both lipid and polymer based pH-sensitive siRNA delivery systems. These systems exhibit pH-sensitive cell membrane destabilization and enhanced intracellular gene silencing efficiency. The pH-sensitive siRNA delivery systems have shown a great promise for efficient delivery of therapeutic siRNA. This review summarizes the concept, design and recent development on pH-sensitive siRNA delivery systems.