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Additional file 1: Figure S1. Characterization of probe. (A) BJH desorption Dv/DW pore volume of mesoporous Fe3O4 NPs. (B) stability of Fe3O4 NPs (0.4 mg/ml) measured for 7 days. Inset: A photo of Fe3O4 NPs in various solutions (from left to right: water, saline, DMEM cell medium and serum). (C) Fourier transform infrared spectra of Fe3O4 and Fe3O4-Peptide. Figure S2. Pathology of Human HCC tissues. H&E staining sections of different human HCC tissue groups (blank, Fe3O4 NPs, FP NPs). Blank: saline, FP NPs: Fe3O4-peptide nanoparticles. Figure S3. probe in human hepatic carcinoma cells. (A) Cell viability of LM3. (B) Cell viability of THLE-3. (C) Fluorescence microscope images of Calcein AM/PI co-stained with different probes (Fe3O4 NPs, FG NPs) at different concentration in acidic environment (pH = 6.5) and neutral environment (pH = 7.4). FG NPs: Fe3O4-GOD nanoparticles. Figure S4. MRI metabolism of the probe in Carcinogen-induced mice models. (A) Comparison of the liver tissues before and at 24 h after injection of FGP NPs at different time points (2, 6, 10, 14, 18, 20 weeks) during liver cancer development. Red-dotted circles represent liver nodules. (B) H&E staining sections of liver nodules of 14-week induced mice and 18-week induced mice detected by MRI. (C) In the contrast of 2-week induced mice ultrasound, 14-week induced mice with liver cirrhosis showed obvious portal vein expansion on ultrasound. And the autopsy of which showed obvious portal vein expansion. (D) Liver function and kidney function of normal mice (control), 8-week induced mice and 12-week induced mice. Figure S5. Ultrasound and 3D-Photoacoustic imaging of the process of inducing liver cancer formation. (A) Ultrasound of at different timepoints (2w, 6w, 10w, 14w, 18w, 20w) of the process of inducing liver cancer formation. (B) 3D-Photoacoustic imaging at different stages (2w, 6w, 10w, 14w, 18w, 20w) of the process of inducing liver cancer formation. Figure S6. Photoacoustic imaging and its signal value of necrosis nodule, HCC nodule and cirrhosis nodule. (A) Autopsy liver necrosis nodules and their corresponding pathology, photoacoustic imaging and its signal value (B) before and after injection of FGP NPs. (C) Autopsy HCC nodules and their corresponding pathology, photoacoustic imaging and its signal value (D) before and after injection of FGP NPs. (E) Autopsy cirrhosis nodules and their corresponding pathology, photoacoustic imaging and its signal value (F) before and after injection of FGP NPs. Figure S7. Photoacoustic imaging and their corresponding pathology. Take two liver lobes from each mouse (n = 7) as the photoacoustic imaging area, and then the detection accuracy of detecting small HCC in complex liver environment is evaluated by whether the photoacoustic imaging area matches the corresponding pathological examination. Among them, the photoacoustic imaging of samples ��� and ��� did not match the pathology, and the other samples were matched. Figure S8. Toxicity evaluated by histological analysis and its Pathoglycemia of FGP NPs. (A) HE stained sections of major organs of mice after treatment with PBS, FP NPs (0.8 mg/ml), FGP NPs (0.8 mg/ml). Scale bar, 100 ��m. (B) Blood glucose level of mice in time of day. Mice (n = 3) was intravenously injected of PBS or FGP NPs at 9:00, respectively.

Additional file 1: Figure S1. EDX analysis of RMnMels. Figure S2. (a)XPS survey spectra. XPS spectra of (b) C1s, (c) N1s and (d) O1s for RMnMels. Figure S3. (a) Hydrodynamicsizes of nanocomposites. (b) Zeta potential of nanocomposites. Figure S4. The linear relationship for the r1relaxivity of RMnMels versus Mnconcentrations. The insets show corresponding T1-weighted MRimages. Figure S5. (a) T1-weightedMR images of mice kidneys and liver prior to and at various time points postintravenous injection of RMnMels at 12 mg/kg body weight. The images wereacquired at 1.5 T.Normalized signal intensities determined from mice (b) kidneys and (c) liver. Figure S6. UV���vis absorption profile ofRMnMels with various mass concentrations. Figure S7. Invitro photoacoustic signal intensities of RMnMels versus solution mass concentrations.The insets show corresponding photoacoustic images. Figure S8. The amount of manganese (Mn) elements per gramof tissue. Figure S9. Cell viability ofPC3 and RAW 264.7 cells after co-incubation with various concentrations ofRMnMels. Figure S10. (a) Optical microscope images of RAW 264.7cells after co-incubation with various concentrations of RMnMels for 12 h. Scale bars, 100 ��m. (b) Opticalmicroscope images of PC3 cells after incubation without (upper) or with (lower)50 ��g/mL RMnMels for 12 h. Scale bars, 100 ��m. FigureS11. (a) Cellular TEM images ofPC3 cells after incubation without (upper) or with (lower) RMnMels at 50 ��g/mLfor 12 h. (b) Tissue TEM images of PC3 tumor tissue slices after intravenous injection of PBS(upper) or RMnMels (lower) for 48 h. Figure S12. Cellular TEM imagesof lipopolysaccharide induced M1-like macrophage after incubation withRMnMels at 50 ��g/mL for 12 h. Figure S13. (a) TEM images ofRMnMels with/without 2.5 mM H2O2 for 72 h. Scale bar, 200 nm.The insets show corresponding digital photographs. (b) UV���vis absorption spectra of RMnMels co-incubation with 2.5 mM H2O2 atdifferent time points. Figure S14. (a) Infrared thermalimages and (b) temperaturevariations of 200 ��g/mL RMnMels aqueous solution during exposure to a 690 nm laser with different powerdensities for 300 s. (c) Infrared thermal images and (d) temperature variations of RMnMels aqueous solution with differentconcentrations during exposure to a 690 nm laser at 500 mW/cm2for 300 s. Figure S15. Photothermal heating curvesof RMnMels (100 ��g/mL) irradiated by 690 nm laser at 500 mW/cm2 over three laser ON/OFF cycles. FigureS16. (a) TEM images of RMnMels solution before and after 690 nm laserirradiation (500 mW/cm2, 30 min). Scale bar, 200 nm. The insets showcorresponding digital photographs. (b) UV���vis absorption spectra of RMnMels aqueoussolutions prior to and after exposure to 690 nm laser irradiation. FigureS17. Flow cytometric assay of the polarization ofRAW 264.7 cells toward M1 phenotype. Figure S18. Body weight curves of PC3 tumor-bearing mice during a periodof 19 days after different treatments. FigureS19. Flow cytometry analysis of tumor immune cells. Gating strategy showingdelineation of (a) singlets cells. (b) numbers indicate the percentages of thecells within the gates. (c) live cells. (d) CD45+ leukocytes. (e) tumor-associatedmacrophages. Figure S20. H&Estained images of mice major organ sections on day 19 after differenttreatments. Scale bar, 100 ��m. FigureS21. Serum biochemical indexes of healthy mice obtained on different timepoint. Table S1. Primer sequences for different genes.

Hypoxia is a hallmark of malignant tumors and often correlates with increasing tumor aggressiveness and poor treatment outcomes. Therefore, early diagnosis and effective killing of hypoxic tumor cells are crucial for successful tumor control. There has been a surge of interdisciplinary research aimed at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. These mainly include hypoxia-active nanoparticles, anti-hypoxia agents, and agents that target biomarkers of tumor hypoxia. Hypoxia-active nanoparticles have been intensively investigated and have demonstrated advanced effects on targeting tumor hypoxia. In this review, we present an overview of the reports published to date on hypoxia-activated prodrugs and their nanoparticle forms used in tumor-targeted therapy. Hypoxia-responsive nanoparticles are inactive during blood circulation and normal physiological conditions but are activated by hypoxia once they extravasate into the hypoxic tumor microenvironment. Their use can enhance the efficiency of tumor chemotherapy, radiotherapy, fluorescence and photoacoustic intensity, and other imaging and therapeutic strategies. By targeting the broad habitats of tumors, rather than tumor-specific receptors, this strategy has the potential to overcome the problem of tumor heterogeneity and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.