Biomembrane-active molecular switches as tools for intracellular drug delivery

Many therapeutic strategies, such as gene therapy and vaccine development require the delivery of polar macromolecules ( e. g. DNA, RNA, and proteins) to intracellular sites at a therapeutic concentration. For such macromolecular therapeutics, cellular membranes constitute a major transport barrier that must be overcome before these drugs can exert their biological activity inside cells. A number of biological organisms, e. g. viruses and toxins, efficiently destabilize the cellular membranes upon a trigger, such as low pH, and facilitate the delivery of their biological cargo to the cytoplasm of host cell. pH-responsive synthetic peptides and polymers have been designed to mimic the function of membrane-destabilizing natural organisms and evaluated as a part of drug delivery systems. In this Review, pH-dependent membrane activity of natural and synthetic systems is reviewed, focussing on fundamental and practical aspects of pH-responsive, membrane-disruptive synthetic polymers in intracellular drug delivery.