Exploring alternative biomedical use of traditional drugs in different disease models is highly important as it can reduce the cost of drug development and overcome several critical issues of traditional chemodrugs such as low chemotherapeutic efficiency, severe side effect, and drug resistance. Disulfiram (DSF), a clinically approved alcohol-aversion drug, was recently demonstrated to feature tumor-growth suppression effect along with the co-administration of Cu²⁺ species, but direct Cu²⁺ administration mode might cause severe toxicity originating from low Cu²⁺ accumulation into the tumor and nonspecific Cu²⁺ distribution-induced cytotoxicity. Based on the intriguing drug-delivery performance of nanoscale metal-organic frameworks (MOFs), we herein construct HKUST nMOFs as the Cu²⁺ self-supplying nanocarriers for efficient delivery of the DSF drug. The mildly acidic condition of tumor microenvironment initially triggered the release of Cu ions from HKUST nMOFs, which further reacted with the encapsulated DSF to form toxic Cu(DDTC)₂ (activation) for tumor chemotherapy. Especially, during the Cu(DDTC)₂ complexation, Cu⁺ species were formed concomitantly, triggering the intratumoral nanocatalytic therapy for the generation of reactive oxygen species to synergistically destroying the tumor cells/tissue. As a result, synergetic tumor-responsive chemotherapy and nanocatalytic therapy are enabled by DSF@HKUST nanodrugs, as demonstrated by the dominant anticancer efficacy with satisfied biocompatibility both in vitro and in vivo. The present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.

探索不同疾病模型中传统药物的替代生物医学用途非常重要，因为它可以降低药物开发的成本并克服传统化学药物的几个关键问题，例如化学治疗效率低，严重的副作用和耐药性。最近证实，临床批准的酒精转化药物双硫仑（DSF）具有抑制肿瘤生长的作用以及与Cu ²⁺物种的共同给药，但是直接Cu ²⁺给药方式可能会导致低铜引起的严重毒性。²⁺累积进入肿瘤和非特异性Cu ²⁺分布诱导的细胞毒性。基于纳米级金属-有机骨架（MOF）令人着迷的药物传递性能，我们在此构建HKUST nMOFs作为Cu ²⁺自给纳米载体，以有效传递DSF药物。肿瘤微环境的弱酸性条件最初触发了HKUST nMOFs释放Cu离子，其进一步与封装的DSF反应形成有毒的Cu（DDTC）₂（激活），用于肿瘤化学治疗。特别是在Cu（DDTC）₂络合过程中，Cu ⁺伴随地形成了两个物种，触发了用于产生活性氧物种的肿瘤内纳米催化疗法，以协同地破坏肿瘤细胞/组织。结果，DSF @ HKUST纳米药物可实现协同的肿瘤反应性化疗和纳米催化疗法，这在体外和体内均具有显着的抗癌功效和令人满意的生物相容性。本工作为具有高生物相容性的肿瘤反应性无毒到有毒的治疗方法提供了复杂的策略。