Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy

Real-time monitoring of hydroxyl radical (& sdot;OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although & sdot;OH probe-integrated CDT agents can track & sdot;OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of & sdot;OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into beta-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2O2) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic & sdot;OH and therefore allowed Fc-CD-AuNCs to in situ self-report & sdot;OH generation without undesired & sdot;OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo. A NIR-II fluorescence-monitored chemodynamic therapy agent (Fc-CD-AuNCs) is prepared by integrating ferrocene (Fc) into beta-cyclodextrin-functionalized gold nanoclusters via host-guest interaction. In addition to producing & sdot;OH, Fenton reaction between redox-active Fc quencher and H2O2 causes Fc oxidation and consequent NIR-II fluorescence recovery, allowing renal-clearable Fc-CD-AuNCs to self-monitor & sdot;OH formation without undesired & sdot;OH consumption.image