A multifunctional cascade bioreactor based on a layered double oxides composite hydrogel for synergetic tumor chemodynamic/starvation/photothermal therapy

Abstract

The field of nanomedicine-catalyzed tumor therapy has achieved a lot of progress; however, overcoming the limitations of the tumor microenvironment (TME) to achieve the desired therapeutic effect remains a major challenge. In this study, a nanocomposite hydrogel (GH@LDO) platform combining the nanozyme CoMnFe-layered double oxides (CoMnFe-LDO) and natural enzyme glucose oxidase (GOX) was engineered to remodel the TME to enhance tumor catalytic therapy. The CoMnFe-LDO is a nanozyme that can convert endogenous H₂O₂ into reactive oxygen species (ROS) and O₂ to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Meanwhile, GOX can catalyze the conversion of glucose and O₂ to gluconic acid and H₂O₂, which not only represses the ATP production of tumor cells to achieve starvation therapy (ST), but also decreases the pH value of TME and supplies extra H₂O₂ to enhance the CDT effect. Furthermore, this well-designed CoMnFe-LDO possessed a high photothermal conversion efficiency of GH@LDO (66.63%), which could promote the generation of ROS to enhance the CDT effect and achieve photothermal therapy (PTT) under near-infrared light irradiation. The GH@LDO hydrogel performes cascade reaction which overcomes the limitation of the TME and achieves satisfactory CDT/ST/PTT synergetic effects in vitro and in vivo. This work provides a new strategy for remodeling the TME using nanomedicine to achieve precise tumor cascaded catalytic therapy. STATEMENT OF SIGNIFICANCE: At present, the focus of tumor therapy has begun to shift from monotherapy to combination therapy for improving the overall therapeutic effect. In this study, we synthesized a CoMnFe-LDO nanozyme composed of multiple transition metal oxides, which demonstrated improved peroxidase and oxidase activities as well as favorable photothermal conversion capability. The CoMnFe-LDO nanozyme was compounded with an injectable GH hydrogel crosslinked by GOX and horseradish peroxidase (HRP). This nanocomposite hydrogel overcame the limitations of weak acidity, H₂O₂, and O₂ levels in the TME and achieved synergetic CDT, ST, and PTT effects based on the cascaded catalytic actions of CoMnFe-LDO and GOX to H₂O₂ and glucose.

Keywords: Cascade reaction; Layered double oxides; Tumor catalytic therapy; Tumor microenvironment remodeling.