A Self‐Monitoring Single‐Atom Copper Nanocapsule for Cascade‐Responsive Tumor Cuproptosis Therapy

Abstract

ABSTRACT Cuproptosis represents a potent anticancer mechanism, yet its translation is hampered by the scarcity of tumor‐selective and efficient copper ion modulators. Herein, we develop a single‐atom copper‐based smart nanocapsule (SNC) that enables cascade‐responsive copper ion release within the tumor microenvironment (TME) for synergistic cuproptosis therapy and self‐monitoring. The SNCs are constructed by anchoring isolated copper atoms within a gold cluster/zeolite framework via the Cu‐imidazole/carboxyl coordination, guaranteeing atomic dispersion and high biostability. Upon encountering the weakly acidic and glutathione‐rich TME, the SNCs undergo sequential ligand protonation and competitive coordination, which synergistically triggers framework disassembly and controlled copper ion release. The intracellularly accumulated copper ions robustly activate the cuproptosis pathway and concurrently facilitate a specific fluorescence recovery of gold clusters for self‐reporting therapeutic monitoring. Both in vitro and in vivo assessments demonstrate high‐efficacy tumor therapy and imaging capabilities without eliciting systemic toxicity. This work pioneers a versatile cuproptosis‐induction platform with broad potentials for advancing diverse biomedical applications.