Chemodynamic
therapy (CDT) has received increasing attention due to its unique tumor microenvironment (TME) responsiveness and minimal adverse side effects, but the
therapeutic effect of CDT alone is always limited due to the low Fenton or Fenton-like reaction efficiency at
tumor sites. Herein, Fe-doped layered double
hydroxide (LDH) nanosheets were synthesized to load the anticancer drug
epigallocatechin-3-O-gallate (EGCG) and then conjugated with
boronic acid-modified
hyaluronic acid for targeted and cooperative chemo-chemodynamic
therapy of
tumors. The formed LDH-EGCG-HA nanoplatforms could specifically target
tumor cells overexpressing CD44 receptors, quickly release
iron ions and EGCG in the TME, and efficiently generate toxic
hydroxyl radicals with the acceleration of Fe3+/Fe2+ cycling in the Fenton reaction by EGCG. The cooperative
cancer cell inhibition effect through
chemotherapy and chemodynamic
therapy was achieved by the significant upregulation of
caspase-3 and p53 expression to induce cell apoptosis, and the deactivation of xCT and GPX-4 to inhibit GSH synthesis and reduce
lipid peroxides for reinforced ferroptosis. In vivo experiments further verified that the intelligently designed LDH-EGCG-HA nanoplatforms had a superior biocompatibility with normal organs with an excellent inhibition efficacy towards
tumors overexpressing CD44 receptors by targeted chemo-chemodynamic
therapy.