Peptide-drug conjugates repolarize glioblastoma-associated macrophages to resensitize chemo-immunotherapy of glioblastoma

作者：Zhi Li, Shaoping Jiang, Jie Wang, Wenpei Li, Jun Yang, Weimin Liu, Huile Gao, Yuanyu Huang, Shaobo Ruan · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adr8841 · 被引用次数：30 · 研究领域：Immune cells in cancer、Nanoplatforms for cancer theranostics、Nanoparticle-Based Drug Delivery

The prevalent tumor-supporting glioblastoma-associated macrophages (GAMs) promote glioblastoma multiforme (GBM) progression and resistance to multiple therapies. Repolarizing GAMs from tumor-supporting to tumor-inhibiting phenotype may troubleshoot. However, sufficient accumulation of drugs at the GBM site is restricted by blood-brain barrier (BBB). Herein, we designed peptide-drug conjugates (PDCs) by conjugating camptothecin or resiquimod to a tandem peptide composed of matrix metalloproteinase 2–responsive peptide and angiopep-2 via disulfonyl-ethyl carbonate/carbamate ( MA PDCs). The mixed self-assembly MA PDCs could recognize low-density lipoprotein receptor–related protein 1 (LRP1) to facilitate BBB transport. Once reaching the GBM site, the responsive peptide would be cleaved to shed the angiopep-2, blocking abluminal LRP1-mediated brain-to-blood efflux and enhancing drug retention. Sequentially, drugs are released under the high level of intracellular glutathione. In vivo studies demonstrated that MA PDCs repolarized GAMs, boosted immune response, and resensitized chemotherapeutic toxicity, offering a much-improved anti-GBM effect. The effectiveness of MA PDCs validates GAMs as therapeutic target and PDCs as versatile brain delivery system with high design flexibility.