GSH Triggered Copper‐Complexes as Nano‐Prodrug for NIR‐II Fluorescence Monitoring Cuproptosis in Tumor Therapy

ABSTRACT Cuproptosis has emerged as a promising paradigm for anticancer therapy. Although various studies have employed copper ionophores to facilitate intracellular copper delivery, these agents primarily promote copper accumulation and trigger subsequent cuproptosis, lack the capacity for real‐time monitoring and dynamic regulation of the therapeutic process. In this study, we designed a series of NIR‐II fluorescent copper‐coordinating ligands, designated as Et‐X. Among them, the optimal candidate was identified based on its superior coordination affinity and used to construct the Et‐DPA‐Cu complex. This complex can release Cu + in response to elevated glutathione levels within the tumor microenvironment, initiating Fenton‐like reaction and inducing cuproptosis. Simultaneously, based on photoinduced electron transfer (PeT) mechanism, the complex exhibits an “off–on” fluorescence transition upon releasing of Cu + , thereby enabling real‐time NIR‐II fluorescence imaging with high contrast. To further enhance tumor selectivity and biocompatibility, the complex was encapsulated within DSPE‐mPEG 5K to form a nano‐prodrug, termed EDCP. Experimental results reveal that EDCP effectively accumulates in tumor tissues via the enhanced permeability and retention (EPR) effect, achieving potent cuproptosis‐mediated tumor suppression while permitting high‐resolution NIR‐II fluorescence imaging. Overall, this work presents a robust nano‐prodrug platform that integrates therapeutic precision and diagnostic capability, holding substantial promise for advanced cancer theranostics.