Construction of Host–Guest Interaction-Based Supramolecular Self-Assemblies for SO ₂ -Augmented Chemodynamic Therapy

Due to the insufficient H 2 O 2 level and the overexpression of glutathione (GSH) in the tumor microenvironment, the in situ Fenton reaction is markedly suppressed, thereby limiting the efficacy of chemodynamic therapy (CDT). To address this challenge, we herein propose an interesting strategy to enhance CDT efficacy by amplifying intracellular oxidative pressure through in situ SO 2 generation. Accordingly, functional supramolecular polymer self-assemblies (SPSAs@PA) were rationally engineered, enabling GSH-responsive SO 2 release accompanied by effective GSH consumption. The released SO 2 disrupts intracellular redox homeostasis and significantly enhances reactive oxygen species (ROS) accumulation, thereby intensifying oxidative stress for SO 2 -augmented CDT. The detailed mechanism involves: (1) upon GSH stimulation, SPSAs@PA rapidly generate SO 2 in situ, leading to pronounced depletion of intracellular GSH; (2) l -ascorbyl palmitate (PA) participates in redox-related reactions with endogenous proteins, promoting the production of additional H 2 O 2 as substrates for the Fenton reaction, thus generating more ·OH; and (3) the elevated oxidative pressure and ROS levels synergistically amplify CDT-induced oxidative damage. Based on this mechanism, SO 2 -augmented CDT can be effectively achieved through in situ SO 2 generation, GSH depletion, and ROS enhancement. Notably, SPSAs@PA exhibited remarkable anticancer efficacy, with cell lethality reaching up to 96% at a concentration of 7 μg/mL of 2,4-dinitrobenzenesulfonyl chloride-modified ferrocene (Fc-DNBS), demonstrating that this strategy of in situ SO 2 -induced oxidative pressure amplification is highly effective for enhancing CDT efficacy in tumor therapy.