Mesothelin targeted nano-system enhanced chemodynamic therapy and tirapazamine chemotherapy via lactate depletion

The enhanced permeability and retention (EPR) effect alone is not enough for nanoparticles to reach the target. Combination of active and passive targeting may be an effective drug delivery route. Hollow ferric-tannic acid complex nanocapsules (HFe-TA) may effectively degrade and release Fe²⁺ ions, and Fe²⁺ ions induce the production of ·OH, however, the fenton reaction needs amount of H₂O₂ to enhance chemodynamic therapy. Due to their deficiencies, such nanoparticles cannot realize intravenous drug delivery. Here, the mesothelin-targeted membrane (MTM) was constructed to realize accurate delivery nano-system, and mesothelin antibody was expressed on the 293T cell membrane to prepare a MTM. Lactate oxidase (Lox) was loaded on HFe-TA to obtain Lox@HFe-TA. Lox@HFe-TA was coated with MTM to develop the MTM nanosystem. Tirapazamine (TPZ) therapy also requires hypoxia circumstance. The MTM nanosystem combined with TPZ can significantly kill tumour cells and inhibit metastasis in vivo and in vitro. We also tested the biological safety of the treatment. In this study, we overcame the EPR defects via the MTM nanosystem, which can realize acute targeted delivery to the tumour site, lactate depletion, promoted reactive oxygen species (ROS) induction, and enhanced the effect of TPZ, demonstrating a potential synergistic combination of cancer therapy with better efficacy and biosafety.