Function toggle of tumor microenvironment responsive nanoagent for highly efficient free radical stress enhanced chemodynamic therapy

In contrast to reactive oxygen species (ROS), the generation of oxygen-irrelevant free radicals is oxygen- and H₂O₂-independent in cell, which can offer novel opportunities to maximum the chemodynamic therapy (CDT) efficacy. Herein, an H₂O₂-independent “functional reversion” strategy based on tumor microenvironment (TME)-toggled C-free radical generation for CDT is developed by confining astaxanthin (ATX) on the NiFe-layered double hydroxide (LDH) nanosheets (denoted as ATX/LDH). The unique ATX/LDH can demonstrate outstanding TME-responsive C-free radical generation performance by proton coupled electron transfer (PCET), owing to the specific ATX activation by unsaturated Fe sites on the LDH nanosheets formed under TME. Significantly, the Brönsted base sites of LDH hydroxide layers can promote the generation of neutral ATX C-free radicals by capturing the protons generated in the ATX activation process. Conversely, ATX/LDH maintain antioxidant performance to prevent normal tissue cancerization due to the synergy of LDH nanosheets and antioxidative ATX. In addition, C-free radical can compromise the antioxidant defense in cells to the maximum extent, compared with ROS. The free radicals burst under TME can significantly elevate free radical stress and induce cancer cell apoptosis. This strategy can realize TME-toggled C free radical generation and perform free radical stress enhanced CDT.