多药耐药是癌症化疗失败的主要原因，传统多药耐药逆转策略由于耐药机制的复杂性而难以取得显著效果。因此，开发具有广谱性的新型逆转耐药策略至关重要。与正常细胞和非耐药癌细胞相比，具有更高水平的活性氧是耐药癌细胞普遍存在的特征。基于这一特点，本研究设计一系列喹唑啉酮-多肽衍生物，其特点是能够响应活性氧进而触发超分子自组装，实现在耐药癌细胞内选择性富集线粒体电子转移链抑制剂，干扰线粒体正常功能，实现逆转耐药作用。后续协同前药特异性激活策略，实现精准杀灭耐药癌细胞，而不引起药物副作用。本研究提出利用耐药癌细胞的共性，即过生产的活性氧作为诱导因子实现逆转耐药，其最大的优势在于克服肿瘤细胞异质性，有望发展成为一种具有普适性的新型逆转肿瘤多药耐药策略。此外，基于超分子自组装的可逆性，本研究将能够提供一种用于克服肿瘤耐药且安全有效的纳米材料。

Multidrug resistance (MDR) is a major challenge to cancer chemotherapy. Various approaches have been developed for fighting against MDR, but all have their own pitfalls. Therefore, a renovated strategy for MDR reduction is urgently needed. Comparing to normal cells and non-drug resistant cancer cells, drug resistant cancer cells possess higher reactive oxygen species (ROS). Based on this unique phenomenon, our proposed research starts with the preparation of quinazolinedione-peptide small molecules, which are oxidized by ROS to trigger supramolecular self-assembly in situ and selectively accumulate inhibitors against mitochondria electron transport chains, and therefore make mitochondria dysfunctional to reverse MDR. Then, the combination of reversal of MDR with specific prodrug activation could selectively kill drug resistant cancer cells without inducing adverse drug resistance. The apparent advantage of this method is to overcome the intra-tumoral heterogeneity based on targeting the over-produced ROS. We envision that the success of this research will serve as a novel strategy and provide an effective nanomaterial for alleviation of MDR in chemotherapy.