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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 (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.)

Lipid peroxidation (LPO) is one of the most damaging processes in chemodynamic therapy (CDT). Although it is well known that polyunsaturated fatty acids (PUFAs) are much more susceptible than saturated or monounsaturated ones to LPO, there is no study exploring the effect of cell membrane unsaturation degree on CDT. Here, we report a self-reinforcing CDT agent (denoted as OA@Fe-SAC@EM NPs), consisting of oleanolic acid (OA)-loaded iron single-atom catalyst (Fe-SAC)-embedded hollow carbon nanospheres encapsulated by an erythrocyte membrane (EM), which promotes LPO to improve chemodynamic efficacy via modulating the degree of membrane unsaturation. Upon uptake of OA@Fe-SAC@EM NPs by cancer cells, Fe-SAC-catalyzed conversion of endogenous hydrogen peroxide into hydroxyl radicals, in addition to initiating the chemodynamic therapeutic process, causes the dissociation of the EM shell and the ensuing release of OA that can enrich cellular membranes with PUFAs, enabling LPO amplification-enhanced CDT., (© 2023 Wiley-VCH GmbH.)

Singlet oxygen ( 1 O 2 ) has a potent anticancer effect, but photosensitized generation of 1 O 2 is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of 1 O 2 -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO 4 2- catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO 4 2- -catalyzed generation of 1 O 2 from H 2 O 2 and protects MoO 4 2- from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H 2 O 2 and 1 O 2 can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent 1 O 2 sensor to achieve monitored tumor CDT., (© 2021 Wiley-VCH GmbH.)