Homologous Cell Membrane-Coated DP-4 Peptide Degrader Boosts USP7 Degradation and Anti-Tumor Activity in Gastric Cancer

Ubiquitin-specific protease 7 (USP7) is a critical deubiquitinase that plays a significant role in promoting tumor cell proliferation and immune evasion, making it an attractive therapeutic target in oncology. Current therapeutic strategies for gastric cancer (GC) often face challenges with drug delivery and specificity, particularly for peptide-based compounds which typically exhibit poor cell permeability. Targeting USP7 offers a promising avenue to disrupt key oncogenic pathways, but effective intracellular delivery of peptide degraders remains a substantial hurdle to overcome for clinical translation.

Researchers designed peptide-based proteolysis-targeting chimeras (p-PROTACs) by utilizing Epstein-Barr nuclear antigen 1 (EBNA1), a natural ligand of USP7, as the targeting moiety. Through screening various E3 ligands, they identified DP-4 as a potent USP7 degrader. To circumvent the inherent permeability issues of peptide degraders, DP-4 was subsequently encapsulated within homologous MKN-45 gastric cancer cell membranes (MM) to create MM@DP-4 nanoparticles. The study then evaluated the intracellular delivery, USP7 degradation efficiency, and functional anti-tumor effects of MM@DP-4 in MKN-45 cells, assessing cellular uptake via flow cytometry and T-cell-mediated killing assays.

The homologous cell membrane coating significantly improved the intracellular delivery of the peptide degrader. MM@DP-4 achieved substantially enhanced cellular uptake compared to free DP-4, demonstrating 60.9% uptake versus 2.50% at 4 hours in MKN-45 cells. This enhanced delivery translated into robust, post-transcriptional USP7 degradation, with MM@DP-4 exhibiting a degradation concentration DC50 of 1.24 μM in MKN-45 cells. Functionally, the enhanced degradation led to significant anti-tumor effects. > MM@DP-4 markedly enhanced T-cell-mediated killing of gastric cancer cells and effectively suppressed their proliferation, highlighting its therapeutic potential. These findings collectively establish DP-4 as a potent peptide-based USP7 degrader and validate homologous cancer cell membrane coating as an effective strategy to boost intracellular delivery and degradation efficacy.