Self‐Assembled Peptide‐Derived Proteolysis‐Targeting Chimera (PROTAC) Nanoparticles for Tumor‐Targeted and Durable PD‐L1 Degradation in Cancer Immunotherapy

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. Self‐assembled peptide‐derived PROTAC nanoparticles (PT‐NPs) are synthesized through peptide self‐assembly, including anti‐PD−L1 peptide, self‐assembling linker and E3 ligase recruiter. The PT‐NPs utilize multivalent binding for PD−L1‐targeted endocytosis, effective degrading PD−L1 receptors in tumor cells via dual degradation mechanisms: direct lysosomal degradation and PROTAC‐mediated degradation, offering a potent approach to cancer immunotherapy.