Coassembly of Enzyme-Responsive Cholate-Conjugated Facially Amphiphilic Polymers

Inspired by the unique self-assembly of bile acid-based facial amphiphiles (FAs), a family of facially amphiphilic cholic acid-derived homopolymers and their coassembled nanoaggregates have been fabricated. The cholate-pendant cationic PC (quaternary amine-based), anionic PA1 (sulfate-based), and PA2 (phosphate-based) polymers individually formed spherical nanoaggregates due to the required hydrophobic/hydrophilic balance. However, the coassembled aggregates of oppositely charged pairs, PC with PA1 or PA2, generated arrays of different nanoaggregates depending on the mixing ratio. Additionally, the polymer–protein–polymer coassembly among two oppositely charged facially amphiphilic polymers and a positively/negatively charged therapeutic protein (lysozyme or insulin) was thoroughly investigated by the UV–vis turbidimetry assay, transmission electron microscopy, and dynamic light scattering. The presence of ester, sulfate, and phosphate groups in PC, PA1, and PA2 makes them susceptible to degradation by esterase, sulfatase, and phosphatase enzymes, respectively. Thus, enzyme-triggered in vitro release of two different therapeutics, small-molecule drugs (doxorubicin, DOX) and biomacromolecules (insulin and lysozyme), has been showcased from the self-assembled and coassembled nanoaggregates in physiological conditions. Overall, the present work successfully demonstrated the development of coassembled nanoaggregates using the two oppositely charged cholate-based FAs, with a promising potential for engineering next-generation enzyme-responsive therapeutic delivery vehicles.