<p>Sonodynamic therapy (SDT) has gained attention as a promising non-invasive cancer treatment strategy due to its localized effects and superior tissue penetration. SDT induces apoptosis and immunogenic cell death (ICD) via the generation of reactive oxygen species (ROS) upon ultrasound irradiation. However, tumor heterogeneity, the immunosuppressive tumor microenvironment, and the limited accumulation of sonosensitizers at the tumor site pose significant challenges to SDT’s therapeutic efficacy. In this study, a tumor-targeting nanosonosensitizer, Zr-HMME-PEG-Linaclotide (HP-LNC), was designed by coordinating the sonosensitizer hematoporphyrin monomethyl ether (HMME) with zirconium (Zr) to form a Zr-HMME complex. Polyethylene glycol (PEG) was used to enhance the complex’s water dispersity and biocompatibility. Finally, linaclotide was conjugated to the nanoplatform through a thiol-maleimide reaction to impart tumor-targeting functionality. This zirconium-incorporated nanosonosensitizer can be readily detected by positron emission tomography (PET) and fluorescence imaging. Comprehensive characterization confirmed the successful synthesis of HP-LNC and its favorable physicochemical properties. In vitro and in vivo studies demonstrated that ultrasound activation significantly enhanced ROS generation, inducing potent cytotoxic effects and ICD through high-mobility group box 1 protein (HMGB1) release and calreticulin (CRT) translocation. PET and fluorescence imaging results revealed efficient accumulation of HP-LNC at the tumor site, excellent in vivo stability for HP-LNC, and effective monitoring of therapeutic progress. Overall, this nanoplatform successfully integrates dual-modal imaging with ROS-mediated therapy, highlighting its substantial potential in multimodal cancer treatment, particularly for colorectal cancer therapy.</p> Graphical Abstract <p></p>