Proton-actuated membrane-destabilizing polyion complex micelles

The efficiency of nucleic acid-based drugs is usually hampered by the fact that, following their uptake by the cell, these drugs end up in acidic organelles (i.e., endosomes/lysosomes) from which they barely escape. This work relates to the preparation and characterization of polyion complex micelles (PICM) formed by the self-assembly of three polyelectrolytes: a diblock cationic copolymer; a membranolytic, methacrylic acid copolymer; and an oligonucleotide. It is demonstrated that a synthetic membrane-active polyanion can be successfully integrated within the structure of PICM to yield well-defined, narrowly distributed micelles (30 nm) with a core/shell architecture. Besides their ability to protect the oligonucleotide against nuclease degradation, PICM partly dissociate under mildly acidic conditions, releasing chain clusters that destabilize bilayer membranes. This association/dissociation behavior illustrates the potential of these pH-sensitive PICM for the transport and efficient delivery of polyionic drugs.