A ratiometric theranostic nanoplatform with acid-triggered drug release and glutathione-activated fluorescence turn-on

Theragnostic nanomedicines that precisely coordinate drug delivery with imaging remain a significant challenge. Here, we report a novel nanoformulation that integrates acid-sensitive drug release with a glutathione (GSH)-activated fluorescence turn-on mechanism for targeted cancer therapy and real-time tracking. Our system is based on folic acid-functionalized zinc oxide quantum dots (QFZnO) loaded with a third-generation Casiopeina drug, IIIGCas, a copper-based coordination compound. Upon reaching the acidic tumor microenvironment, IIIGCas is released, subsequent intracellular GSH reduction converts the non-fluorescent Cu(II) complex into a highly fluorescent Cu(I) adduct, activating a distinct “turn-ON” signal. Computational studies reveal that this redox switch suppresses photoinduced electron transfer, restoring the emission of the drug's intrinsic curcumin-derived fluorophore and amplifying its fluorescence by sixfold. This mechanism creates a dual-emission system, enabling the simultaneous ratiometric tracking of nanocarrier (QFZnO) localization and drug activation. The nanoplatform demonstrated enhanced potency, showing statistically significant cytotoxicity in cervical and triple-negative breast cancer cell lines at far lower doses than free IIIGCas. In vivo, using zebrafish xenograft models, it achieved precise tumor targeting and a 90 % reduction in primary tumor area, while effectively illuminating secondary micrometastases. This work provides a generalizable blueprint for designing intelligent metal-complex delivery systems that optically report their own therapeutic activation in real-time.