Insufficient oxygenation(hypoxia),acidic pH(acidification)and increased level of hydrogen peroxide(H2O2)are recognized as three common characteristics of the tumor microenvironment(TME),owing to the rapid growth of tumor cells,upregulated glycolytic metabolism and abnormal tumor vasculature.They jointly not only promote tumor angiogenesis,invasion and metastasis,but also contributes to tumor treatment resistance.New approaches for improving tumor oxygenation are of great importance for enhancing oxygen-involved photodynamic response in cancer treatment.In the present study,anionic albumin templated gold nanoclusters(BSA-AuNCs),cationic polyelectrolyte stablized MnO2 nanoparticles(PAHMnO 2 NPs),and negatively charged submicron microbubbles(SubMBs)were first prepared.Then they were assembled through layer-by-layer method and generate AuNCs-MnO2-SubMBs(Figure 1).The asobtained multifunctional AuNCs-MnO2-SubMBs nanocomposites demonstrated good stablity and biocompatibility,and focused ultrasound mediated blood-tumor barrier opening allowed the efficient delivery of nanocomposites to the tumor region.The high reactivity of MnO2 towards endogenous hydrogen peroxide(H2O2)within the acidic TME could realize TME-responsive MR imaging and CT/NIRF imaging.The produced O2 at tumor site in situ could effectively alleviate tumor hypoxia,decrease acidification and inhibit tumor angiogenesis.More importantly,O2 could remarkably improve the photodynamic efficiency of AuNCs under 630 nm laser irradiation.The developed AuNCs-MnO2-SubMBs will open up new avenues for construction of intelligent nanoplatforms with comprehensive TME regulation ability and developing more precise and efficient theranostics against hypoxic solid tumors.