Cascade-enhanced persistent luminescence for monitoring iron metabolism during ferroptosis-based therapy

Ferroptosis-based cancer therapy offers a promising alternative to traditional chemotherapy due to the susceptibility of cancer cells to ferroptosis and the minimal development of drug resistance. Accurate and highly sensitive imaging of ferroptosis is essential for evaluating its specificity and antineoplastic efficacy, as well as for elucidating its underlying mechanisms. However, background fluorescence from living tissues significantly limits the sensitivity of current in vivo fluorescence imaging techniques for ferroptosis. In this study, a ferroptosis theranostic agent is developed that employs cascade-enhanced persistent luminescence (PersL) to sensitively monitor ferroptosis during treatment without interference from autofluorescence. This agent comprises Zn_1.3Ga_1.4Sn_0.3O₄:Cr³⁺,Y³⁺ (ZGSO) nanocrystals encapsulated within Fe-silica hybrid layers, forming passion fruit-like structures. In the acidic tumor microenvironment, the Fe-silica layer degrades, releasing Fe³⁺. In the upstream pathways of ferroptosis, Fe³⁺ is reduced to Fe²⁺, thereby promoting further ferroptotic progression. During this iron metabolism process, the PersL of ZGSO nanocrystals is sequentially enhanced. The release of Fe³⁺ enhances PersL by removing the light-absorbing Fe-silica layer. Additionally, competition for electrons between Fe³⁺ and the defect levels of ZGSO during PersL emission quenches the signal; thus, Fe³⁺ redox leads to further PersL enhancement. This cascade-enhanced, autofluorescence-free imaging strategy enables visualization of iron metabolism during ferroptosis and achieves an in vivo signal-to-background ratio as high as 87. Moreover, the ultrasmall ZGSO nanocrystals can be efficiently cleared via the kidneys after degradation, significantly improving biosafety. This approach provides new insights into the mechanisms of ferroptosis and highlights its potential in theranostic applications.