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

  • J Control Release. 2025 Dec 30:391:114591. doi: 10.1016/j.jconrel.2025.114591.
Guangyu Rong  1 ,  Yuhan Li  2 ,  Fang Zhu  2 ,  Yiteng Lu  1 ,  Zhengwang Sun  3 ,  Jiaxu Hong  4 ,  Yiyun Cheng  5
Affiliations
  • 1. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
  • 2. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 3. Department of Musculoskeletal Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China. Electronic address: [email protected].
  • 4. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; National Health Commission of Myopia and Related Eye Diseases, Shanghai 200031, China; Shanghai Key Laboratory of Rare Disease Gene Editing and Cell Therapy, Shanghai Engineering Research Center of Synthetic Immunology, Shanghai 200032, China; Department of Ophthalmology, Children's Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201102, China. Electronic address: [email protected].
  • 5. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: [email protected].
PMID: 41478376 DOI: 10.1016/j.jconrel.2025.114591
Abstract

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.

Keywords
Co-assembly; Fluorous peptides; Intracellular peptide delivery; PROTAC; Tumor therapy.
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