内源性过氧化氢缺乏和细胞内酸度不足通常是限制化学动力学治疗（CDT）的两个重要因素。在这里，我们报道了一种谷胱甘肽响应性纳米药物，它可以通过同时抑制双酶为 CDT 提供合适的环境。该纳米药物是通过将新型硫化氢供体封装在由谷胱甘肽响应性两亲聚合物组装的纳米胶束中而构建的。该纳米药物响应细胞内谷胱甘肽，可以有效释放活性成分硫化氢、碳酸酐酶抑制剂和二茂铁。硫化氢可以通过抑制过氧化氢酶和增强糖酵解来增加过氧化氢和乳酸的浓度。碳酸酐酶抑制剂可以通过抑制碳酸酐酶IX的功能进一步诱发瘤内酸中毒。因此，纳米药物可以为二茂铁介导的芬顿反应提供更有效的反应条件，产生丰富的有毒羟基自由基。体内结果表明，增强CDT与酸中毒相结合可以有效抑制肿瘤生长。这种纳米医学设计提供了一种有前景的双酶抑制策略，以增强 CDT 的抗肿瘤功效。版权所有 © 2024。由 Elsevier B.V 出版。

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.Copyright © 2024. Published by Elsevier B.V.