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Real‐time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe‐integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self‐consumption of ⋅OH. Here, we report the facile fabrication of a self‐monitored chemodynamic agent (denoted as Fc‐CD‐AuNCs) by incorporating ferrocene (Fc) into β‐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 ⋅OH and therefore allowed Fc‐CD‐AuNCs to in situ self‐report ⋅OH generation without undesired ⋅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. [ABSTRACT FROM AUTHOR]

In vivo H2O2 visualization is crucial for disease diagnosis. Catalytic reaction‐based probes show potential in H2O2 detection, yet their in vivo application remains challenging because catalysts always require a specific pH to function and cellular glutathione (GSH) may suppress signaling by depletion of hydroxyl radicals and oxidized substrates. Here, a microenvironment‐tailored catalytic nanoprobe (MTCN) comprising Fe2+, citric acid (CA), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) diammonium salt (ABTS), and downconversion nanoparticles in the liposomal cavity as well as a reference dye in the lipid membrane is reported, which utilizes the selective permeability of the liposomal membrane to offer a favorable pH for Fe2+ catalyst with the aid of CA and to avoid GSH‐triggered signal loss by preventing entry of GSH into the cavity. The MTCN displays a large NIR‐II fluorescence (FL) ratio between 1550 and 1080 nm (FL1550Em,808Ex/FL1080Em,980Ex), but a small photoacoustic (PA) ratio between 808 and 1048 nm (PA808/PA1048). Upon exposure of MTCN to H2O2, catalytic conversion of ABTS into its oxidized form ABTS·+ with 808 nm absorption causes a noticeable increment in PA808/PA1048 accompanied by an apparent decrement in FL1550Em,808Ex/FL1080Em,980Ex, enabling bimodal ratiometric imaging of H2O2 in the tumor and lymphatic metastasis. [ABSTRACT FROM AUTHOR]

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into β-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 (H 2 O 2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅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., (© 2023 Wiley-VCH GmbH.)

Ferrous iron (Fe 2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe 2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe 0 nanoparticles (Fe 0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe 0 -siRNA NPs are degraded to release Fe 2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O 2 ). The accompanied O 2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe 0 -siRNA NPs. In addition to initiating chemodynamic process, Fe 2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT., (© 2023 Wiley-VCH GmbH.)