Catalytic cascade transformations, which occur in spatially constrained tumor environment to generate therapeutic moieties from prodrugs or intrinsic species, are highly desirable for precise cancer therapy. Nevertheless, it is high challenging to engineer a cascade nanoreactor with tumor microenvironment (TME)-responsive capability for synergistic tumor therapy. Inspired by the biocatalytic cascades in biological processes, here, a tumor-specific nanoreactor was established to activate cascade reactions for oxidative stress-augmented chemotherapy by the integration of an artificial enzyme, Pt(IV)-based prodrug (Pt(IV)), with Cu(II)-based metal-organic frameworks (CuMOF). Upon internalization of CuMOF@Pt(IV) by tumor cells, in addition to chemotherapeutic effect, the activated cisplatin by glutathione (GSH) reduction is capable of acting as an artificial enzyme to elevate the hydrogen peroxide (H₂O₂) level through cascade reactions for augmenting the therapeutic efficacy of Cu⁺-mediated chemodynamic therapy (CDT). Meanwhile, CuMOF@Pt(IV) specifically deplete overexpressed GSH at tumor sites, thus amplifying tumor oxidative stress, and finally leading to augmented antitumor efficacy. The orchestrated cooperative effect of chemotherapy and oxidative stress presents splendid therapeutic efficacy on tumor-bearing mice with negligible adverse effects. Therefore, this cascade nanoreactor provides exciting opportunities to develop complementary therapeutic modalities for precise cancer treatment.

催化级联转化发生在空间受限的肿瘤环境中以从前药或内在物质产生治疗部分，对于精确的癌症治疗非常理想。然而，设计具有肿瘤微环境（TME）响应能力的级联纳米反应器用于协同肿瘤治疗具有很高的挑战性。受生物过程中生物催化级联反应的启发，这里建立了一个肿瘤特异性纳米反应器，通过整合人工酶、基于 Pt(IV) 的前药 (Pt(IV))来激活氧化应激增强化疗的级联反应，具有基于 Cu(II) 的金属有机骨架 (CuMOF)。CuMOF@Pt(IV) 被肿瘤细胞内化后，除了化疗作用外，激活的通过谷胱甘肽 (GSH) 还原产生的顺铂能够充当人工酶，通过级联反应提高过氧化氢 (H ₂ O ₂ ) 水平，从而增强 Cu ⁺介导的化学动力学疗法 (CDT)的治疗效果。同时，CuMOF@Pt(IV)特异性地消耗肿瘤​​部位过表达的谷胱甘肽，从而放大肿瘤氧化应激，最终增强抗肿瘤功效。化疗和氧化应激的协同作用对荷瘤小鼠具有极好的治疗效果，而副作用可忽略不计。因此，这种级联纳米反应器为开发用于精确癌症治疗的补充治疗方式提供了令人兴奋的机会。