Self-Amplifying Oxidative Burst and Antioxidant Collapse Enabled by Redox-Responsive Curcumin-Polyprodrug Nanoplatform for Enhanced Antitumor Therapy

Abstract Tumor therapy is challenged by heterogeneity, drug resistance, and systemic toxicity. Targeting tumor redox imbalance using pro-oxidants offers a promising strategy, but natural pro-oxidants such as curcumin (Cur) and cinnamaldehyde (CA) suffer from poor solubility and bioavailability. Here, we developed two redox dual-responsive Cur-based polyprodrug nanoparticles, PCSC NPs with thioether linkages and PCSSC NPs with disulfide bonds, incorporating a ROS-sensitive CA-derived crosslinker (CASOH). The distinct linkages enable sequential ROS/GSH-responsive cleavage and programmed drug release, while CASOH promotes rapid nanoparticle disassembly. This design triggers a self-amplifying oxidative stress cascade, leading to lipid peroxidation, GPX4 downregulation, mitochondrial membrane depolarization, and increased lysosomal membrane permeabilization, thereby activating apoptotic and autophagic cell death. In 4T1 tumor-bearing mice, both NPs achieved efficient tumor accumulation, potent antitumor activity with up to 85% tumor inhibition, and minimal systemic toxicity. These findings demonstrate a redox-programmable polyprodrug platform for adaptive drug release and amplified oxidative damage in cancer therapy.