Tumor microenvironment-responsive nanocarrier based on VO${}_x$ nanozyme amplify oxidative stress for tumor therapy

The construction of a novel nanocarrier that can break the redox balance in tumor cell is a promising anti-tumor strategy. Herein, a tumor microenvironment (TME)-responsive nanocarrier VC@Lipo is rationally designed by embedding ultrasmall VO${}_x$ nanozyme and photosensitizer chlorin e6 (Ce6) into liposomes. The size of VC@Lipo nanocarrier is ≈35 nm and can be degraded in the weakly acidic environment of TME. The VO${}_x$ nanozyme exhibits peroxidase-like activity and generates highly toxic hydroxyl radical ∙OH through Fenton-like reaction and ${}^1$O${}_2$ in the presence of H${}_2$O${}_2$ independent of light, and more ${}^1$O${}_2$ can be generated by the photodynamic effect of Ce6. In addition, the VO${}_x$ nanozyme can effectively deplete intracellular overexpressed glutathione (GSH) through redox reactions. In vivo experiments demonstrate that the nanocarrier shows excellent biocompatibility, presents the largest enrichment at the tumor site after 6 h of intravenous injection into mice with the highest tumor inhibition rate of 54.18% after laser irradiation. Compared with the single treatment mode, VC@Lipo shows the best synergistic effect of chemodynamic-photodynamic therapy. This work provides a new paradigm for nanocatalytic therapy of cancer and is expected to provide new ideas for precision medicine in cancer. (© 2023 Wiley‐VCH GmbH)