Photodynamic therapy (
PDT) and
radiotherapy (RT) are
oxygen-dependent treatment strategies for solid
tumors in clinics. However, the hypoxic tumor microenvironment induced by uncontrolled
cancer cell proliferation significantly reduces the therapeutic efficacy of these strategies. Here, we rationally constructed
indocyanine green (ICG)-loaded ultrasmall
gold nanoclusters (Au NCs-ICG) as
theranostic nanozymes for modulating tumor hypoxia and augmenting
cancer PDT and RT, respectively. The constructed Au NC-ICG nanozymes with an ultrasmall particle size (∼1 nm) exhibited favorable renal clearance performance, high substrate affinity (Km≈ 2 mM) and good
catalase-like activity (Vmax≈ 4.55 × 10-3 mM s-1). In 4T1
tumor-bearing mouse models, high
tumor accumulation of Au NC-ICG nanozymes was clearly visualized by near-infrared fluorescence, photoacoustic and computed tomography imaging, showing the potential for the monitoring and guidance of
PDT and RT. In addition, the Au NCs-ICG nanozymes effectively decomposed intratumoral H2O2 into O2 for overcoming
hypoxia and subsequently enhancing
PDT and RT, respectively. Moreover, the inherent X-ray absorption capacity of Au NCs-ICG greatly deposited radiation energy within the
tumor region and further improved
cancer RT. The integration of multimodal imaging, tumor hypoxia regulation, and effective
therapy into ultrasmall Au NCs-ICG nanozymes shows great potential for
cancer theranostic applications.