Triggered Inversion of Dual Responsive Diblock Copolypeptide Vesicles

We report the synthesis of amphiphilic poly(l-methionine sulfoxide)_x-b-poly(dehydroalanine)_y, diblock copolypeptides, M^O_xA^DH_y, and their self-assembly into submicrometer-diameter unilamellar vesicles in aqueous media. The formation of vesicles was observed over an unprecedented range of copolypeptide compositions due to the unique properties and chain conformations of A^DH hydrophobic segments. These copolypeptides incorporate two distinct thiol reactive components where each segment can respond differently to a single thiol stimulus. Incubation of M^O₃₅A^DH₃₀ vesicles with glutathione under intracellular mimetic conditions resulted in vesicle disruption and release of cargo. Further, incubation of M^O₃₅A^DH₃₀ vesicles with thiolglycolic acid resulted in a reversal of amphipilicity and successful in situ inversion of the vesicle assemblies. This conversion of biomimetic polymer vesicles into stable inverted vesicles using a biologically relevant stimulus at physiological pH and temperature is unprecedented. These results provide insights toward the development of advanced functional synthetic assemblies with potential uses in biology and medicine.