铁死亡、铜死亡和化学动力学疗法（CDT）的结合将成为肿瘤诊断和强化治疗的潜在策略。然而，在谷胱甘肽过量、酸度有限和内源性过氧化氢不足的肿瘤微环境（TME）中，催化离子缺乏特异性递送以及芬顿反应效率低，治疗效果受到严重限制。在这项工作中，对碳酸酐酶 IX (CA IX) 抑制剂对羧基苯磺酰胺 (BS) 在第 5 代聚酰胺胺树枝状聚合物的表面进行修饰，以负载过氧化铜纳米粒子，该纳米粒子与铁 (Fe) 络合 -单宁酸 (TF) 网络用于靶向磁共振 (MR) 成像，并通过调节 TME 增强铁死亡/铜死亡/CDT。形成的CuO2@G5-BS/TF纳米复合物平均尺寸为39.4 nm，可以在肿瘤部位特异性积累，并通过肿瘤细胞上过表达的BS和CA IX之间的特异性相互作用被转移性4T1细胞有效内化。同时，抑制CA IX活性不仅可以降低细胞内pH值，加速Fe3/Cu2的释放、H2O2自供和Fenton反应，还可以通过减轻TME中细胞外的酸性来抑制肿瘤转移。此外，细胞内谷胱甘肽（GSH）还原Fe3/Cu2可以进一步放大ROS的产生并增强CDT疗效，而GSH的消耗反过来又可以抑制GPX-4介导的抗氧化反应诱导铁死亡，从而产生有效的治疗效果。体内实验结果表明，CuO2@G5-BS/TF可以提供更好的肿瘤MR成像，有效抑制4T1乳腺肿瘤的生长和转移，并且被代谢而无明显的全身毒性。因此，CuO2@G5-BS/TF纳米复合物为靶向MR成像和增强三阴性乳腺癌的铁死亡/铜死亡/CDT提供了一种新方法。意义陈述：利用树枝状大分子和金属酚醛体系的优势，合成了平均尺寸为39.4 nm的稳定CuO2@G5-BS/TF纳米复合物，以有效负载Fe3和CuO2纳米粒子，用于TNBC治疗和MR成像。 CuO2@G5-BS/TF纳米复合物可以通过与BS特异性结合来靶向过表达CAIX的肿瘤细胞，抑制CAIX活性不仅可以降低细胞内pH，加速Fe3/Cu2释放、H2O2自供和Fenton反应，还通过减轻细胞外酸性来抑制肿瘤转移。细胞内GSH还原Fe3/Cu2可以进一步放大·OH的产生，而GSH的消耗又可以抑制GPX-4介导的抗氧化反应而诱导铁死亡，通过肿瘤微环境调节增强铁死亡/铜死亡/CDT，从而产生有效的治疗效果.版权所有 © 2024。由 Elsevier Ltd 出版。

The combination of ferroptosis, cuproptosis, and chemodynamic therapy (CDT) would be a potential strategy for tumor diagnosis and enhanced treatment. However, the therapeutic effect was severely limited by the lack of specific delivery of catalytic ions and the low Fenton reaction efficiency in tumor microenvironment (TME) with excess glutathione, limited acidity and insufficient endogenous hydrogen peroxide. In this work, p-carboxybenzenesulfonamide (BS), a carbonic anhydrase IX (CA IX) inhibitor, was modified on the surface of generation-5 poly(amidoamine) dendrimer to load copper peroxide nanoparticles, which were complexed with iron (Fe)-tannic acid (TF) networks for targeted magnetic resonance (MR) imaging and enhanced ferroptosis/cuproptosis/CDT by regulating TME. The formed CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm could be specifically accumulated at tumor site and effectively internalized by metastatic 4T1 cells via the specific interaction between BS and CA IX over-expressed on tumor cells. Meanwhile, the inhibition of CA IX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity in TME. Moreover, the reduction of Fe3+/Cu2+ by intracellular glutathione (GSH) could further amplify ROS generation and enhance CDT efficacy, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy. In vivo experimental results demonstrated that CuO2@G5-BS/TF could provide better tumor MR imaging, effectively inhibit the growth and metastasis of 4T1 breast tumors, and be metabolized without significant systemic toxicity. Thus, CuO2@G5-BS/TF nanocomplexes provided a new approach for targeted MR imaging and enhanced ferroptosis/cuproptosis/CDT of triple-negative breast cancer. STATEMENT OF SIGNIFICANCE: Taking the advantage of dendrimer and metal-phenolic system, stable CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm were synthesized to efficiently load Fe3+ and CuO2 nanoparticles for TNBC treatment and MR imaging. CuO2@G5-BS/TF nanocomplexes could target tumor cells overexpressing CAIX via the specific binding with BS, and the inhibition of CAIX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity. The reduction of Fe3+/Cu2+ by intracellular GSH could further amplify ·OH generation, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy by enhanced ferroptosis/cuproptosis/CDT via tumor microenvironment regulation.Copyright © 2024. Published by Elsevier Ltd.