<p>High concentrations of glutathione (GSH) in the tumor microenvironment (TME) represent a promising target for the development of polyurethane (PU)-based redox-responsive drug delivery systems. A series of 3-indolopyrazole acetamide derivatives were designed and synthesized in this study. The anti-proliferative activities of these compounds were evaluated in tumor cell lines, and the small molecule <b>S11</b> (IC₅₀ = 2.64&#xa0;μM) was identified as a potent inhibitor of human chronic myeloid leukemia K562 cells. To overcome the challenges of poor solubility and limited stability associated with the hydrophobic small molecule <b>S11</b>, polyurethane nanocapsules containing disulfide bonds (S–S) were innovatively synthesized. Subsequently, drug-loaded polyurethane nanocapsules (<b>S11-1</b>) were synthesized via interfacial polymerization. In vitro experimental results indicated that these nanocapsules exhibit enhanced drug release performance compared to free <b>S11</b>, with a GSH-responsive release mechanism. Furthermore, <b>S11-1</b> effectively promotes K562 cell apoptosis, elevates intracellular Reactive Oxygen Species (ROS) levels, and induces mitochondrial membrane potential depolarization (MMP). Overall, <b>S11-1</b> demonstrates considerable potential in enhancing drug delivery efficiency, improving targeting precision, and modulating biological activity.</p> Graphical abstract <p>In this study, 21 indolopyrazole acetamide derivatives were synthesized, among which compound <b>S11</b> (IC₅₀ = 2.64&#xa0;μM) demonstrated potent antiproliferative activity against K562 cells. To address the limitations of poor aqueous solubility and insufficient stability associated with <b>S11</b>, drug-loaded polyurethane nanocapsules (<b>S11-1</b>) were developed via interfacial polymerization. Mechanistic investigations revealed that <b>S11-1</b> exerts its antitumor effect by modulating intracellular ROS levels and mitochondrial membrane potential.</p> <p></p>