Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy.

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins. Simultaneous degradation of two oncogenic proteins by PROTACs can yield synergistic therapeutic effects. Here, we developed a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) that leverages supramolecular self-assembly for cancer therapy. By conjugating PD-L1- and Bcl-xL-binding peptides to fluorous tags, we generated carrier-free nanoparticles that enter cells via macropinocytosis and achieve efficient endosomal escape, mediating simultaneous degradation of both extracellular PD-L1 and cytosolic Bcl-xL through the ubiquitin-proteasome system. Our results demonstrate that DFP-PROTAC coordinately restores antitumor immunity and apoptotic sensitivity while achieving superior antitumor efficacy with excellent biocompatibility in B16-F10 melanoma-bearing mice, highlighting its therapeutic potential for cancer treatment. This modular fluorous platform offers a versatile strategy for degrading multiple protein targets in the treatment of various diseases.