Tumor microenvironment (TME)-modulating nanoreactor for multiply enhanced chemodynamic therapy synergized with chemotherapy, starvation, and photothermal therapy

Abstract

The combination of chemotherapy (CT) and chemodynamic therapy (CDT) via nanoscale drug delivery systems has great potential for tumor therapy. Nevertheless, the low intracellular H₂O₂ and high reductive glutathione (GSH) levels, as well as the mildly acidic conditions (pH 5.8–6.8) of the tumor microenvironment (TME) still limit their further applications. To tackle these problems, a TME-modulating nanoreactor (denoted as Fe₃O₄-DOX@PDA-GOx@HA, FDPGH) was developed through a simple and practicable method to achieve multiply enhanced CDT synergized with CT, starvation therapy (ST), and photothermal therapy (PTT). Upon cellular uptake, the hyaluronic acid (HA) and PDA shells rapidly collapsed to release Fe₃O₄, glucose oxidase (GOx) and doxorubicin (DOX), and the overexpressed GSH could promote the reduction of Fe³⁺ to Fe²⁺, resulting in CDT activation. GOx-driven oxidation reaction not only produced H₂O₂ for enhanced CDT, but also killed tumor cells by initiating ST. In addition, the acid amplification caused by gluconic acid production in turn accelerated the degradation of FDPGH, promoting the Fenton reaction to enhance CDT. Most importantly, the nanoreactor had excellent photothermal performance to achieve PTT and PTT-enhanced CDT with the release of DOX into tumor tissue to achieve enhanced CT. This novel cascade nanoreactor with TME-modulating capability is intended to provide further inspiration for multimodal treatment paradigms.