Ultrafast self-assembled supramolecular nanoparticles for enhanced chemodynamic therapy and ferroptosis through lactic acid metabolism regulation

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.

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

Enzyme functionalized PEOz modified magnetic polydopamine with enhanced penetration for cascade-augmented synergistic tumor therapy

Due to the powerful redox homeostasis and inefficiency of monotherapy, chemodynamic therapy (CDT) is clinically limited. Despite great efforts, the design of CDT nanosystems with specific H2O2 homeostasis and effective integration of multiple treatments remains a great challenge. Therefore, herein, we engineer a novel pH-responsive nanocatalyst to disrupt intracellular H2O2 homeostasis through consuming glutathione (GSH), elevating H2O2 and restraining H2O2 elimination, as well as achieving a combination of CDT and chemotherapy (CT) through sensitized DSF. In the formulation, amplified CDT synergized enhanced CT significantly, strengthening the tumor therapeutic efficacy in vitro and in vivo. This work not only solves intracellular redox homeostasis disruption, but also realizes the re-use of old drugs, providing new insights for CDT-based multimodal cancer therapy.

pH-responsive nanocatalyst for enhancing cancer therapy via H2O2 homeostasis disruption and disulfiram sensitization.

Reactive oxygen species (ROS)-induced cancer therapy is extremely limited by tumor hypoxia, insufficient endogenous hydrogen peroxide (H2O2), overexpressed glutathione (GSH), and slower reaction rate. To address these challenges, in this paper, a hybrid nanomedicine (CaO2@Cu/ZIF-8-ICG@LA, CCZIL) is developed using a copper-based metal-organic framework (Cu/ZIF-8) for cancer synergistic therapy. H2O2/O2 self-supplementing, GSH-depleting, and photothermal properties multiply amplify ROS generation. Moreover, disulfiram (DSF) chemotherapy (CT) was activated by chelating with Cu2+ to synergize therapy. This novel strategy has enormous potential for ROS-involved synergistic antitumor therapy.

Wenqiu Li

Papers

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

Enzyme functionalized PEOz modified magnetic polydopamine with enhanced penetration for cascade-augmented synergistic tumor therapy

pH-responsive nanocatalyst for enhancing cancer therapy via H2O2 homeostasis disruption and disulfiram sensitization.

Copper-Based Metal-Organic Framework Enables ROS Amplification and Drug Potency Activation.