Precise Synthesis of Star-Shaped Redox-Responsive Segmented Polyurethanes with Controlled Arm Sequences for Drug Delivery

The elegant hierarchical structures of biomacromolecules have promoted the pursuits of synthetic polymers with ordered monomer sequences and diverse topological architectures, which are in the initial stage. Here, a four-arm star-shaped segmented polyurethane (PU) with a controlled block sequence of amphiphilic seven-segment multifunctional arms containing a disulfide bond was prepared via a grafting-onto strategy, where the sequence-defined arms were synthesized by a diisocyanate-based liquid-phase iterative methodology and then conjugated onto four alkyne-functionalized pentaerythritol cores through click chemistry. The star-shaped PU can self-assemble into micelles in aqueous solution as the linear arm. Moreover, the four-arm star-shaped architecture endows self-assembled micelles with higher stability under various physiological conditions and enhanced redox-responsive performance, making them promising candidates for drug delivery. The experiments show that drug-loaded star-shaped PU micelles possess accelerated stimuli-responsive release profiles, optimized tissue distribution, and improved anticancer efficacy in vitro and in vivo in comparison with linear polymer micelles. This work demonstrates that advanced architectures of precise linear polymers hold tremendous potential for the structural regulation and performance adjustment of aggregation structures, opening the perspectives for the structural and functional design of next-generation materials.