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Updated: Jun 6, 2025
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Self-Assembled Peptide-Derived Proteolysis-Targeting Chimera (PROTAC) Nanoparticles for Tumor-Targeted and Durable
Yujeong Moon1,2,3, Hanhee Cho1, Jinseong Kim1
1College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
Abstract:
Proteolysis-targeting chimeras (PROTACs) are a promising technique for the specific and durable degradation of cancer-related proteins via the ubiquitin-proteasome system in cancer treatment. However, the therapeutic efficacy of PROTACs is restricted due to their hydrophobicity, poor cell permeability and insufficient tumor-targeting ability. Herein, we develop the self-assembled peptide-derived PROTAC nanoparticles (PT-NPs) for precise and durable programmed death-ligand 1 (PD-L1) degradation in targeted tumors. The PT-NPs with an average size of 211.8 nm are formed through the self-assembly of amphiphilic peptide-derived PROTAC (CLQKTPKQC-FF-ALAPYIP), comprising a PD-L1-targeting 'CLQKTPKQC', self-assembling linker 'FF' and E3 ligase recruiting 'ALAPYIP'. Particularly, PT-NPs strongly bind to tumor cell surface PD-L1 to form PD-L1/PT-NPs complex, then internalized through receptor-mediated endocytosis and degraded in lysosomes. Second, free PROTACs released from PT-NPs to the cytoplasm further induce the durable proteolysis of cytoplasmic PD-L1 via the ubiquitin-proteasome system. In colon tumor models, intravenously injected PT-NPs accumulate significantly at targeted tumor tissues through nanoparticle-derived passive and active targeting. At the targeted tumor tissues, PT-NPs promote durable PD-L1 degradation and ultimately trigger a substantial antitumor immune response. Collectively, this study provides valuable insights into the rational design of self-assembled peptide-derived PROTAC nanoparticles to ensure noticeable accuracy and enhanced efficacy in cancer treatment.
Insights
Researchers developed self-assembled peptide-derived PROTAC nanoparticles (PT-NPs) for targeted protein degradation. These PT-NPs enhance cancer treatment by precisely degrading programmed death-ligand 1 (PD-L1) in tumors, improving therapeutic efficacy.
Area of Science:
- Biotechnology
- Nanotechnology
- Oncology
Background:
- Proteolysis-targeting chimeras (PROTACs) offer specific protein degradation for cancer therapy but face challenges like poor cell permeability and tumor targeting.
- Existing PROTACs require improvement for enhanced therapeutic efficacy in cancer treatment.
Purpose of the Study:
- To develop self-assembled peptide-derived PROTAC nanoparticles (PT-NPs) for precise and durable degradation of programmed death-ligand 1 (PD-L1) in targeted tumors.
- To overcome the limitations of conventional PROTACs by enhancing tumor targeting and cell permeability.
Main Methods:
- Self-assembly of amphiphilic peptide-derived PROTACs into nanoparticles (PT-NPs) with an average size of 211.8 nm.
- Utilizing PT-NPs for targeted binding to tumor cell surface PD-L1, followed by receptor-mediated endocytosis and lysosomal degradation.
- Investigating the release of free PROTACs from PT-NPs for cytoplasmic PD-L1 degradation via the ubiquitin-proteasome system.
Main Results:
- PT-NPs demonstrated significant accumulation in targeted tumor tissues through passive and active targeting after intravenous injection.
- The developed PT-NPs effectively promoted durable PD-L1 degradation within targeted tumor tissues.
- This targeted degradation ultimately triggered a substantial antitumor immune response in colon tumor models.
Conclusions:
- Self-assembled peptide-derived PROTAC nanoparticles offer a promising strategy for precise and durable PD-L1 degradation in cancer therapy.
- The rational design of PT-NPs enhances accuracy and efficacy, providing valuable insights for developing advanced cancer treatments.
- PT-NPs represent a significant advancement in overcoming PROTAC limitations for improved cancer treatment outcomes.
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