Colorectal cancer is one of the malignant tumors with high morbidity and lethality. Its efficient diagnosis and treatment has important significance. In this study, the orthotopic cancer model mouse, which could perfectly simulate clinical inflammatory colorectal cancer, was constructed by chemical induction. Based on this model, a new pH/ultrasonic dual-response, step-targeting and precisely controlled-release enteric-coated granule was designed for the combined sonodynamic (SDT)-chemotherapy. The enteric-coated granule was fabricated by enwrapping carboxymethyl chitosan (CMC) on folic acid-modified phospholipid (SLB-FA) encapsulating mesoporous silicon-coated gold nanoparticles loaded with chlorin (Ce6) and doxorubicin hydrochloride (DOX), titled as Au@mSiO2/Ce6/DOX/SLB-FA@CMC (GMCDS-FA@CMC). The diameter of the Au@mSiO2/Ce6/DOX/SLB-FA (GMCDS-FA) nanoprobe was 61.21 nm and that of the GMCDS-FA@CMC enteric-coated granule was 1.1 μm. MTT results showed that the cell survival rate was still as high as 76.55 ± 1.27% when the concentration of GMCDS-FA was up to 200 μg mL-1, which can indicate the low cytotoxicity of the nanoprobe. According to CT imaging, the enteric-coated granule had the highest concentration in the colorectum of the orthotopic cancer mouse after 7-9 h with oral administration, and was nearly metabolized out of the body after 24 h. The in vitro and in vivo experiments showed that the targeting enteric-coated granule had the best effect of treatment and desired prognosis after combined SDT-chemotherapy.