Modification‐Response Integrated Modules Driven Cyclization‐Dependent Prodrug Self‐Assembly for Reshaping Pro‐Apoptotic Tumor Redox Homeostasis

Affected by the complexity and heterogeneity of the tumor redox microenvironment, chemotherapy often fails to achieve satisfactory clinical outcomes. Modular design of prodrug nanoassemblies presents tremendous potential in upgrading the therapeutic index of chemotherapeutic agents. Given the biochemical vulnerability of tumor redox homeostasis, we fabricated five-membered cyclic chalcogenide-linked paclitaxel prodrug nanoassemblies, which realized tumor site-specific activation and reshaped the pro-apoptotic tumor redox homeostasis. Cyclic diselenide and cyclic disulfide bonds integrated the modification modules and response modules to minimize the utilization of non-pharmacodynamic moieties and increase druggability. Importantly, the modification-response integrated modules could simultaneously block the glutathione-glutathione peroxidase (GSH/GPx) antioxidant system and amplify reactive oxygen species (ROS) generation. The reshaping of the tumor redox homeostasis cascade triggered the loss of mitochondrial membrane potential and apoptosis of tumor cells, which synergistically potentiated the antitumor effects of paclitaxel. Such an intelligent prodrug nanoplatform brought new perspectives for constructing advanced antitumor nanomedicines with significant clinical research value.