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

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 (^MAPDCs). The mixed self-assembly ^MAPDCs 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 ^MAPDCs repolarized GAMs, boosted immune response, and resensitized chemotherapeutic toxicity, offering a much-improved anti-GBM effect. The effectiveness of ^MAPDCs validates GAMs as therapeutic target and PDCs as versatile brain delivery system with high design flexibility.