Glutathione-programmed in situ catalyst self-assembly activates tumor-specific NO storm for gasodynamic therapy

Nitric oxide (NO) demonstrates promising prospects in tumor therapy, nevertheless, critical challenges remain in precisely modulating its concentration-dependent duality, minimizing off-target toxicity, and overcoming technical barriers in clinical translation. Herein, a glutathione (GSH)-responsive metal-organic framework, CuSNP, is constructed to realize the tumor-specific and burst generation of NO by on-site synthesizing catalysts within tumors. Triggered by the elevated GSH in cancer cells which could confer cellular resistance to NO-induced oxidative stress, CuSNP first undergoes structural disassembly, resulting in the release of free ligand nitroprusside and cuprous ions. Subsequently, leveraging the intrinsically abundant GSH, cuprous ions spontaneously chelate with GSH molecules to form Cu-GSH complex in situ, which acts as specific catalysts to enable burst release of NO from nitroprusside. Simultaneously, cuprous ions decompose hydrogen peroxide (H₂O₂) into hydroxyl radicals (·OH) that can sensitize cancer cells to NO-induced mitochondrial dysfunction and DNA damage. The clinical drug-based framework enables precise and effective release of NO and reactive oxygen species within neoplastic cells, achieving significant suppression of tumor growth, while maintaining systemic safety. Through programming of GSH, this work establishes a platform for precise and efficient delivery of NO to tumors, providing novel insights into NO-based therapy.