一种同源细胞膜包被的基于肽的USP7降解剂增强胃癌中的降解效率和抗肿瘤活性
A homologous cell membrane-coated peptide-based USP7 degrader enhances degradation efficiency and anti-tumor activity in gastric Cancer.
摘要(中文译文)
泛素特异性蛋白酶7（USP7）是一种致癌性去泛素化酶，可促进肿瘤细胞增殖和免疫逃逸，因而成为有前景的治疗靶点。本研究利用USP7的天然配体Epstein-Barr核抗原1（EBNA1）作为靶向部分，设计了基于多肽的蛋白水解靶向嵌合体（p-PROTACs）。通过筛选多种E3连接酶配体，我们鉴定出一种强效USP7降解剂DP-4，能够在胃癌（GC）细胞中诱导USP7降解。为克服多肽降解剂固有的通透性限制，我们将DP-4进一步包裹于同源MKN-45细胞膜（MM）中，制备MM@DP-4纳米颗粒，显著改善了细胞内递送。与游离DP-4相比，MM@DP-4的细胞摄取大幅增强（4小时时为60.9%对2.50%），并在MKN-45细胞中以1.24 μM的降解浓度（DC）促进强效的转录后USP7降解。在功能上，MM@DP-4增强了T细胞介导的杀伤作用并抑制了胃癌细胞增殖。总之，我们的研究确立了DP-4作为一种强效的基于多肽的USP7降解剂，并证明同源癌细胞膜包覆是提高细胞内递送和降解 efficacy 的有效策略，支持将USP7降解作为胃癌的有前景的治疗方法。
Abstract
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 DC 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.
如何引用
AMA
Cong-Cong Ma, Cheng-Yun Jin, Nin-Jie Guo, Hong-Min Liu, Qian-Ge Yin, Yu-Bing Wang, et al. A homologous cell membrane-coated peptide-based USP7 degrader enhances degradation efficiency and anti-tumor activity in gastric Cancer.. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110067.
APA
Cong-Cong Ma, Cheng-Yun Jin, Nin-Jie Guo, Hong-Min Liu, Qian-Ge Yin, Yu-Bing Wang, et al (2026). A homologous cell membrane-coated peptide-based USP7 degrader enhances degradation efficiency and anti-tumor activity in gastric Cancer.. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110067
GB/T 7714
Cong-Cong Ma, Cheng-Yun Jin, Nin-Jie Guo, Hong-Min Liu, Qian-Ge Yin, Yu-Bing Wang, et al. A homologous cell membrane-coated peptide-based USP7 degrader enhances degradation efficiency and anti-tumor activity in gastric Cancer.[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110067.
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