Redox Dual-Responsive Drug Delivery System with Cascade of Reactive Oxygen Species Self-Generation for Enhanced Cancer Chemotherapy.

Conventional chemotherapy is significantly hampered by the inherent hydrophobicity of chemotherapeutic agents, limited tumor-specific targeting, and inadequate intratumoral accumulation, all of which undermine its clinical efficacy. Nonselective distribution of cytotoxic agents leads to suboptimal drug concentrations within tumor tissues, causing systemic toxicity in healthy organs. Tumor microenvironment-responsive nanoplatforms offer a promising strategy for enhancing specificity and efficacy. This study demonstrates the successful development of a nanodrug delivery system, CASS@PTX nanoparticles, where CASS is a cinnamaldehyde-based, disulfide-containing polymer engineered with dual-stimulus responsiveness to glutathione (GSH) depletion and reactive oxygen species (ROS) amplification. This system disrupts intracellular redox homeostasis in tumor cells, triggering the release of encapsulated paclitaxel (PTX) while enhancing chemotherapeutic efficacy through redox-dependent sensitization. GSH consumption and ROS overproduction create a prooxidative microenvironment that enhances PTX-induced apoptosis. Preclinical validation using in vitro cytotoxicity assays and in vivo tumor models demonstrates potent synergistic anti-tumor effects with minimal systemic toxicity. This cascading ROS self-generation strategy represents a promising approach for overcoming multidrug resistance and improving the therapeutic outcomes of cancer chemotherapy.