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Honglei Hu,1,2,* Shuting Zheng,1,2,* Meirong Hou,1,2 Kai Zhu,1,2 Chuyao Chen,1 Zede Wu,1,2 Li Qi,3 Yunyan Ren,1 Bin Wu,4 Yikai Xu,1 Chenggong Yan,1,5 Bingxia Zhao2,6 1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Medical Image Processing, Guangdong Province Engineering Laboratory for Medical Imaging and Diagnostic Technology, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Institute of Respiratory Diseases, Respiratory Department, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 6Experimental Education/Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bingxia Zhao; Yikai Xu, Tel +86 20 61647272; +86 20 62787333, Email bingxiaz@gmail.com; yikaixu917@gmail.comBackground: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research.Methods: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies.Results: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy).Conclusion: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.Keywords: Au@Cu-Sb-S nanoparticle, phototherapy, radiotherapy, spectral CT, photoacoustic imaging