As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)-and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both in vitro and in vivo results demonstrate that, compared with nitrogenmonodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.

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.

In vivo H2 O 2 visualization is crucial for disease diagnosis. Catalytic reactionbased probes show potential in H 2 O 2 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 Fe 2+ , citric acid (CA), 2,2′-azino-bis(3ethylbenzothiazoline-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 Fe 2+ 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 (FL 1550Em,808Ex /FL 1080Em,980Ex ), but a small photoacoustic (PA) ratio between 808 and 1048 nm (PA 808 /PA 1048 ). Upon exposure of MTCN to H 2 O 2 , catalytic conversion of ABTS into its oxidized form ABTS• + with 808 nm absorption causes a noticeable increment in PA 808 /PA 1048 accompanied by an apparent decrement in FL 1550Em,808Ex /FL 1080Em,980Ex , enabling bimodal ratiometric imaging of H 2 O 2 in the tumor and lymphatic metastasis.

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 downregulationenhanced CDT.

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 singleatom 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.

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 downregulationenhanced CDT.