Chiral CuxOS@Fe‐MOFs for Enhanced Cancer Therapy

Abstract Here, the development of chiral D‐/L‐Cu_xOS nanoparticle‐engineered metal–organic frameworks (Fe‐MIL‐88B‐NH₂), denoted as D‐/L‐Cu_xOS@Fe‐MOFs, for cuproptosis and ferroptosis synergistic therapy is described. The D‐/L‐Cu_xOS@Fe‐MOF displayed intense circular dichroism (CD) bands at 488 nm due to the chirality transfer from chiral penicillamine ligands. Chiral D‐/L‐Cu_xOS@Fe‐MOF showed tumor microenvironment‐triggered catalytic therapeutic activity by simultaneously depleting L‐glutathione (GSH) and generating potent reactive oxygen species in cancer cells. In vivo experimental results synchronously demonstrated D‐Cu_xOS@Fe‐MOF with higher efficiency of cancer therapy. The findings revealed that copper/iron ions released from chiral D‐Cu_xOS@Fe‐MOF induced augmented oxidative stress and potent ferroptosis, which synergizes with cuproptosis for enhanced cancer therapy. The synergistic index for D‐Cu_xOS@Fe‐MOF is determined to be 1.94, while L‐Cu_xOS@Fe‐MOF and D,L‐Cu_xOS@Fe‐MOF with 1.75 and 1.84, respectively. To the best of the knowledge, this is the first report of a chiral nanomaterial capable of inducing synergistic ferroptosis‐cuproptosis therapy for cancers. The results should invigorate studies pursuing the rational design of chiral nanomaterials for efficacious cancer therapy based on cuproptosis and ferroptosis.