Raman Self‐Tracking Copper Metal‐Organic Framework‐Based Nanoplatform for Cuproptosis Cancer Therapy

ABSTRACT Cuproptosis represents a promising strategy for cancer therapy, yet its clinical translation is hampered by unexpected deactivation and off‐target toxicity of copper ions during their delivery to tumors. We developed a copper metal‐organic framework‐based nanoplatform (CuF) with H 2 O 2 responsiveness and Raman self‐tracking capability for cuproptosis‐mediated antitumor therapy. CuF was prepared by coordinating Cu 2+ with an alkyne‐bearing ligand, followed by PEGylation and incorporation of an iron‐based catalyst. CuF undergoes catalyst‐mediated oxidative cleavage of alkynyl bonds under tumor‐associated elevated H 2 O 2 levels, causing CuF degradation and Cu 2+ release. Released Cu 2+ causes copper overload in tumor cells, thereby inducing potent cuproptosis. Meanwhile, the resultant aldehydes and acids generated by the oxidative cleavage of alkynes can further synergistically potentiate cuproptosis. Consequently, CuF demonstrated high antitumor efficacy in a 4T1 tumor‐bearing mouse model (with a tumor inhibition rate of 91%). Moreover, alkynes in the metal‐organic framework (MOF) backbone provided an intrinsically enhanced Raman signal, enabling label‐free self‐tracking of CuF distribution and degradation in cells and tissue sections through Raman imaging. Overall, this work not only provides a new paradigm for cuproptosis‐based anticancer agents, but also offers a versatile strategy for engineering H 2 O 2 responsive materials and Raman imaging nanoplatforms.