Reactive oxygen species (ROS) are highly enriched in pathological microenvironments such as inflammation, tumors, and ischemia-reperfusion, providing an endogenous trigger for on-demand drug release, degradation, and clearance. The thioketal (TK) moiety is stable under normal physiological conditions but undergoes oxidative cleavage in elevated ROS environments, making it a foundational motif for designing ROS-responsive polymers. The TK-based polymers, including linear poly(thioketal) (PTK), polyurethanes, and hyperbranched polymers, enable precise control of degradation kinetics, mechanical properties, and drug-release profiles by adjusting parameters such as TK content, backbone hydrophilic-hydrophobic balance, and branching architecture. These polymers have been fabricated into hydrogels, micro/nanoparticles, electrospun fibers, and porous scaffolds demonstrating synergistic ROS-scavenging and stimulus-responsive release in models of acute lung injury, wound repair, myocardial infarction, spinal cord injury, and neuronal regeneration. This Viewpoint summarizes the design strategies, structure-property relationships, and biomedical applications of TK-based polymers, highlights major challenges including ROS heterogeneity in vivo, biosafety of degradation byproducts, and scalable synthesis, and proposes perspectives to advance the TK-based polymers toward clinical and industrial translation.
Zhang et al. (Mon,) studied this question.