Sequence-Dependent Mesophase Cascades in Dual-Responsive Polymeric Micelles

Abstract Stimuli-responsive polymeric assemblies capable of undergoing controlled structural transformations offer powerful opportunities for the design of advanced functional materials. Here, we report a modular strategy for programming sequence-dependent mesophase transitions in polymeric micellar formulations through the co-assembly of diblock and triblock amphiphiles bearing orthogonally responsive end-groups. By combining amphiphiles with distinct molecular architectures and pH- and enzyme-responsive functionalities, we generated mixed micellar systems that undergo an initial mesophase transition from micelles to a hydrogel upon exposure to acidic conditions, followed by a subsequent enzyme-triggered transformation into soluble polymers. Importantly, reversing the order of introducing the stimuli resulted in an alternative multistep response pathway, in which selective enzymatic degradation of the triblock amphiphiles produces diblock-based micelles that, upon lowering the pH, subsequently undergo acid-induced hydrolysis into soluble polymer chains. These findings demonstrate that both the composition of the co-assembled amphiphiles and the sequence of external stimuli dictate the resulting transformation pathway and kinetics. Overall, this work establishes a general approach for designing programmable multi-responsive polymeric formulations that exhibit cascade mesophase transitions through the mixing of amphiphiles with orthogonal reactivities. Such systems provide a promising platform for the development of advanced delivery systems, including orally administered formulations that transition from circulating micelles to hydrogel drug depots and ultimately degrade into readily cleared soluble polymers.