Protein Degradation Nanoparticles for Intraoperative Fluorescence Diagnosis and Postoperative Adjuvant Therapy of Solid Tumors

Fluorescence-guided surgery is challenged by nonspecific fluorescence signaling of the conventional probes, leading to incomplete tumor resection. Moreover, chemotherapy-mediated adjuvant therapy is frequently compromised by systemic toxicity and drug resistance. In this study, we developed a sequential theranostic chimera (namely SEQTAC) for sequentially activating intraoperative tumor margin diagnosis and postoperative residual tumor clearance. The SEQTAC was rationally designed by covalently integrating an enzyme-labile hemicyanine derivative (namely HCy-Br) with a thioketal bond-modified proteolysis-targeting chimera (PROTAC) of BRD4. Upon spray administration, the SEQTAC can be internalized by tumor cells and specifically activated by cathepsin B in the lysosomes. The HCy-Br fluorophore was rapidly lighted up for intraoperative diagnosis of tumor burden and fluorescence imaging-guided tumor resection. After postoperative spraying, the HCy-Br fluorophore generated singlet oxygen upon 655 nm laser irradiation to perform photodynamic therapy and restore the PROTAC for BRD4 degradation in tumor cells, and thus enabled postoperative dissection of the unresectable tumor residue. The SEQTAC significantly inhibited the tumor relapse and elongated animal survival in mouse models of breast and glioblastoma tumors, which provided a promising platform for precise tumor surgery and postoperative tumor management.