Comprehensively Optimizing Fenton Reaction Factors for Antitumor Chemodynamic Therapy by Charge-Reversal Theranostics

Chemodynamic therapy (CDT) is a highly tumor-specific treatment, while its efficacy is compromised by the intratumoral Fenton reaction efficiency, which is determined by the following reaction factors, including the availability of Fenton ions (e.g., Fe²⁺), the amount of H₂O₂, and the degree of acidity. Synchronous optimization of these factors is a big challenge for efficient CDT. Herein, a strategy of comprehensively optimizing Fenton reaction factors was developed for traceable multistage augmented CDT by charge-reversal theranostics. The customized pH-responsive poly(ethylene)glycol-poly(β-amino esters) (PEG-PAE) micelle (PM) was prepared as the carrier. Glucose oxidase (GOx), Fe²⁺, and pH-responsive second near-infrared (NIR-II) LET-1052 probe were coloaded by PM to obtain the final theranostics. The activity of metastable Fe²⁺ remained by the unsaturated coordination with PEG-PAE. Then tumor accumulation and exposure of Fe²⁺ were achieved by charge-reversal cationization of PEG-PAE, which was further enhanced by a GOx catalysis-triggered pH decrease. Together with the abundant H₂O₂ generation and pH decrease through GOx catalysis, the limiting factors of the Fenton reaction were comprehensively optimized, achieving the enhanced CDT both in vitro and in vivo. These findings provide a strategy for comprehensively optimizing intratumoral Fenton reaction factors to overcome the intrinsic drawbacks of current CDT.