Enzyme-Triggered Cargo Release from Methionine Sulfoxide Containing Copolypeptide Vesicles

We have developed a facile, scalable method for preparation of enzyme-responsive copolypeptide vesicles that requires no protecting groups or expensive components. We designed amphiphilic copolypeptides containing segments of water-soluble methionine sulfoxide, M, residues that were prepared by synthesis of a fully hydrophobic precursor diblock copolypeptide, poly(L-methionine)(65)-b-poly(L-leucine(0.5)-stat-L-phenylalanine(0.5))(20), M-65(L-0.5/F-0.5)(20), followed by its direct oxidation in water to give the amphiphilic M derivative, M-65(O)(L-0.5/F-0.5)(20). Assembly of M-65(O)(L-0.5/F-0.5)(20) in water gave vesicles with average diameters of a few micrometers that could then be extruded to nanoscale diameters. The M-O segments in the vesicles were found to be substrates for reductase enzymes, which regenerated hydrophobic M segments and resulted in a change in supramolecular morphology that caused vesicle disruption and release of cargos.