A homologous cell membrane-coated peptide-based USP7 degrader enhances degradation efficiency and anti-tumor activity in gastric Cancer.

Ubiquitin-specific protease 7 (USP7) is an oncogenic deubiquitinase that promotes tumor cell proliferation and immune evasion, making it a promising therapeutic target. Here, we designed peptide-based proteolysis-targeting chimeras (p-PROTACs) by leveraging Epstein-Barr nuclear antigen 1 (EBNA1), a natural ligand of USP7, as the targeting moiety. By screening multiple E3 ligands, we identified a potent USP7 degrader, DP-4, capable of inducing USP7 degradation in gastric cancer (GC) cells. To overcome the intrinsic permeability limitation of peptide degraders, DP-4 was further packaged into homologous MKN-45 cell membranes (MM) to generate MM@DP-4 nanoparticles, which markedly improved intracellular delivery. MM@DP-4 achieved substantially enhanced cellular uptake compared with free DP-4 (60.9% vs 2.50% at 4 h) and promoted robust, post-transcriptional USP7 degradation with a DC50 of 1.24 μM in MKN-45 cells. Functionally, MM@DP-4 enhanced T-cell-mediated killing and suppressed gastric cancer cell proliferation. Collectively, our findings establishes DP-4 as a potent peptide-based USP7 degrader and demonstrates that homologous cancer cell membrane coating is an effective strategy to boost intracellular delivery and degradation efficacy, supporting USP7 degradation as a promising therapeutic approach for GC.