Tailoring albumin-based theranostic PROTACs nanoparticles for enhanced NIR-II bioimaging and synergistic cancer chemo-phototherapy

PROteolysis TArgeting Chimeras (PROTACs), a developing therapeutic tool designed to dictate target proteins for proteolysis through hijacking the ubiquitin–proteasome system, show potential for cancer therapy. However, unfavorable solubility and poor permeability of traditional PROTACs lead to low bioavailability and insufficient tumor distribution, which limit their clinical applications. Herein, we report a tridentate molecular probe (PROTAC-Cy7) by a three-in-one molecular designing strategy, which integrated a warhead that binds to MCL-1, the E3 ligase ligand pomalidomide and a heptamethine cyanine linker connecting the warhead and the ligand into the same scaffold. Then, bovine serum albumin (BSA) nanoparticles (NPs) with excellent biocompatibility, nonantigenic and biosafety were utilized to manufacture water-insoluble PROTAC-Cy7. The prepared PROTAC-Cy7@BSA NPs demonstrated tumor targeting and efficient degradation of MCL-1 through specific binding to MCL-1 receptors, which are overexpressed in multiple tumors. Moreover, PROTAC-Cy7@BSA NPs can be successfully used for near-infrared-II (NIR-II) noninvasively biomedical vascular imaging and to perform tumor resection guided by intraoperative real-time imaging. Under 808 nm laser irradiation, PROTAC-Cy7@BSA NPs exhibited synergistic Chemo-Phototherapy and showed perfect tumor suppression with 100% survival rate throughout the course of 60-day monitoring period. Our work provides a simple and feasible strategy for designing multifunctional drugs to have imaging-guided tumor-targeted multimodal therapy.