Dual Reduction/Acid-Responsive Disassembly and Thermoresponsive Tunability of Degradable Double Hydrophilic Block Copolymer

[Image: see text] We report a thermoresponsive double hydrophilic block copolymer degradable in response to dual reduction and acidic pH at dual locations. The copolymer consists of a poly(ethylene oxide) block covalently connected through an acid-labile acetal linkage with a thermoresponsive polymethacrylate block containing pendant oligo(ethylene oxide) and disulfide groups. The copolymer undergoes temperature-driven self-assembly in water to form nanoassemblies with acetal linkages at the core/corona interface and disulfide pendants in the core, exhibiting dual reduction/acid responses at dual locations. The physically assembled nanoaggregates are converted to disulfide-core-crosslinked nanogels through disulfide–thiol exchange reaction, retaining enhanced colloidal stability, yet degraded to water-soluble unimers upon reduction/acid-responsive degradation. Further, the copolymer exhibits improved tunability of thermoresponsive property upon the cleavage of junction acetal and pendant disulfide linkages individually and in combined manner. This work suggests that dual location dual reduction/acid-responsive degradation is a versatile strategy toward effective drug delivery exhibiting disulfide-core-crosslinking capability and disassembly as well as improved thermoresponsive tunability.