An Activatable Nanoenzyme Reactor for Coenhanced Chemodynamic and Starving Therapy Against Tumor Hypoxia and Antioxidant Defense System

It is critical to improve the efficiency of cancer therapy with minimized side effects.Chemodynamic therapy(CDT)is a tumor therapeutic strategy designed to generate abundant reactive oxygen species(ROS)at tumor sites through a Fenton or Fenton-like reaction.Recently,this developing scheme has demonstrated an incredible promise for tumor therapy.The process involved could induce cell death without the input of external energy,and this could only occur via the conversion of hydrogen peroxide(H_(2)O_(2))to hydroxyl radicals(·OH).Although Fenton or Fenton-like reactions are being exploited for CDT,along with an application of oxidation reactions to supplement H_(2)O_(2),it has been proven that in cancer cells,the high levels of the existing antioxidants could suppress CDT via·OH depletion,and,unfortunately,tumor hypoxia also inhibits the oxidation reactions.Herein,the authors aimed to fabricate an activatable nanoenzyme reactor(NER)to solve this challenge.Fluorescent reporters(FRs)and bioenzyme glucose oxidase(GOX)were coassembled on nanozyme MnO_(2) nanosheets,which was enwrapped by the tumor-targeting material,hyaluronic acid(HA).NER was internalized explicitly by cancer cells through ligand/receptor recognitionmediated endocytosis,followed by intracellular hyaluronidase(HAase)-dependent activation.As a result,the oxygen level was improved,and the antioxidants were depleted,leading to the promotion of glucose consumption and an increase in·OH level.Thus,the NER exhibited multiple effects to induce coenhanced,chemodynamic and starving therapy against tumor hypoxia and antioxidant defense system to achieve a favorable targeted tumor therapeutic,via these rigorously highly effective,and targeted biochemical reactions both in an in vitro cultured cancer cells systemor in an in vivo mice tumor model.