Conventional methods for controlling self-assembly are generally based on the change in hydrophilic/hydrophobic volume fraction of diblock or triblock copolymers, which suffer from low structural diversity and limited chemical tunability. Inspired by nature, segmented multiblock copolymers (MBCs) offer unparalleled opportunities for engineering of biomimetic nanomaterials with tailored properties. However, the self-assembly of MBCs remains largely unexplored and poorly understood. In this study, we report a segmentation-mediated self-assembly strategy to manipulate the morphology of protein-mimic responsive MBCs by facilely altering the block numbers while holding the amphiphilicity constant. In particular, we found that an increased number of nearly alternating biodegradable poly(ε-caprolactone) and hydrophilic polyethylene glycol segments drives micelle-to-worm-to-vesicle transition. Moreover, the L-cystine residue-enriched interlayer of assemblies enables a depolymerizationinduced morphology reversion, resulting in a redox-hyper-responsive property and ultrafast intracellular drug release. Both experimental and computational results provide a new insight into the self-assembly of macromolecules and propose a convenient approach to the construction of smart nanoassemblies with controlled architectures.

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To overcome the spatiotemporal barriers to conventional stimuli-responsive polymeric materials, we report a photo-responsive self-reducible polymer with a built-in photo-locked stimulus precursor derived from dithiothreitol. The smart polymer could hierarchically self-assemble into a layered vesicular structure in an aqueous solution, and undergo a self-cleavage of l-cystine residues in the backbone, in response to reducing moieties uncaged by ultraviolet light in the side chains. The photo-generation of stimulus in situ can potentially overcome the steric hindrance and temporal limitation, leading to a site-specific and ultrafast release of payloads for effective delivery of therapeutics. Our work provides a new approach to the development of smart responsive biodegradable polymers.