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. A theragnostic nanoformulation exhibits “turn-ON” fluorescence response upon reduction by GSH, while acidic pH triggers an ipsochromic shift enabling ratiometric fluorescence analysis. In zebrafish breast cancer xenograft, this ratiometric approach allows precise localization of primary tumors via a marked fluorescence increase in the blue-fluorescent channel, while secondary tumors are detected by elevated emission in green-fluorescent channel. • This nanoplatform integrates acid-triggered drug release. • Redox conversion Cu(II) to Cu(I) suppresses charge transfer, turning ON fluorescence. • Simultaneously monitoring nanocarrier localization and drug activation. • Superior cytotoxicity in cancer cells at significantly lower doses than the free drug. • In vivo shows 90 % primary tumor reduction and illumination of micrometastases.