Biomolecule-tailored chiral nickel oxide nanozymes amplify autophagy-mediated tumor ablation via synergistic photodynamic-chemodynamic therapy

Chiral nanomaterial-mediated phototherapy has attracted attention as an emerging tumor treatment method. In this study, we synthesized chiral nickel oxide (L/D-Cys-NiO) photosensitizers via surface modulation using chiral cysteine molecules, thereby improving the biocompatibility and significantly enhancing the efficacy of photodynamic-chemodynamic therapy. L/D-Cys-NiO can selectively stimulate the production of reactive oxygen species and hydroxyl radicals, providing synergistic therapy in tumor cells with 4-5-fold greater efficacy than conventional phototherapy. L/D-Cys-NiO can also effectively prevent the infiltrative growth and metastasis of tumor cells by reducing their migration and invasiveness by nearly 40 %. In vivo immunohistochemical assays and high-throughput proteomic analysis confirmed that D-Cys-NiO exhibited stronger enhanced permeability and retention effects and induced more significant autophagic behavior than L-Cys-NiO, suggesting a chirality-dependent enhanced autophagy pathway for tumor ablation during photodynamic-chemodynamic synergistic therapy. We expect that these findings will provide exceptional insights into next-generation tumor photosensitizer designs, focusing on the regulation of autophagy in tumor cells through chirality-dependent photoinduction.