癌症的多药耐药(MDR)是各种化疗方法成功的主要障碍之一，也是大多数癌症死亡的原因。开发有效的方法以克服MDR对于癌症的高效化疗仍然是极为必要的。通过传递与线粒体DNA相互作用的靶向抗癌药物被认为是一个有效的策略，因为线粒体的DNA修复能力相对较弱，可以逆转癌症的MDR。在这里，我们报道了一个多聚前药，它可以使用叶酸(FA)和四苯基膦(TPP)靶向基，分别顺序靶向癌细胞和线粒体。它们被连接到由聚[寡聚(乙二醇)甲基乙醚甲基丙烯酸酯] (POEGMA)和共聚单体含有肉桂醛(CNM)和多柔比星(DOX)组成的两性共聚物前药的末端基团上。在自组装成适当尺寸(∼30 nm)的胶束之后，这些胶束被称为TF@CNM + DOX，经静脉注射后可以积累在肿瘤组织中。经过FA介导的内吞作用，内体的酸度(∼pH 5)可以触发CNM从TF@CNM + DOX胶束中释放，随后通过TPP靶向增强进入线粒体。这促进了活性氧(ROS)的过量产生，随后可以增强细胞内氧化应激并触发ROS响应性的DOX释放到线粒体中。TF@CNM + DOX在没有观察到明显副作用的情况下，展现了抑制DOX耐药MCF-7 ADR肿瘤生长的巨大潜力。因此，以肿瘤和线粒体的双重靶向为特点的多聚前药的设计代表了一种理想的策略，可以通过提高细胞内的氧化水平和ROS响应性药物释放来治疗MDR肿瘤。

The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.