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.
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.
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