Heterodimeric prodrug nanoassembly overcomes chemoresistance and ignites immunotherapy in glioblastoma
Guanting Li, Shunzhe Zheng, Penghui Wei, Haonan Li, Meixiu Lu, Xuegang Niu, Jiebo Li, Huimin Wang, Wen Huang, Chenyu Ding, Yuanxiang Lin, Yang Zhu, Dezhi Kang
Journal：CHEMICAL ENGINEERING JOURNAL
IF：13.2
DOI：10.1016/j.cej.2026.176873
PMID：
Published：2026-04-30
research field：肿瘤学癌症生物学免疫治疗药物递送纳米医学表观遗传学
Abstract
The blood-brain barrier (BBB) strictly limits therapeutic options for glioblastoma (GBM), rendering temozolomide (TMZ) the only first-line chemotherapeutic option. However, chronic TMZ exposure inevitably elicits acquired resistance, driven by upregulated O 6 -methylguanine-DNA methyltransferase (MGMT) expression and hyperactive DNA repair machinery. This resistance phenotype concurrently exacerbates the immunosuppressive tumor microenvironment (TME), rendering tumors refractory to immune checkpoint blockade (ICB) therapies. Here, we identified the epigenetic reader BRD4 as a critical orchestrator of chemoresistance and TME immunosuppression. Leveraging this insight, we synthesized a disulfide-bridged heterodimer (DOX-SS-JQ-1) comprising the genotoxic doxorubicin (DOX) and the BRD4 inhibitor JQ-1. Functionalized with the BBB-penetrating T7 peptide, DOX-SS-JQ-1 self-assembled into carrier-free sHPNAs. Notably, sHPNAs achieved precise GBM targeting and tumor-specific activation, triggering profound apoptosis via catastrophic DNA damage. Concurrently, sHPNAs amplified tumor mutational burden and neoantigen load, repolarizing the TME from an immunologically “cold” to a “hot” state. When combined with ICB, sHPNAs significantly curbed tumor invasiveness and prolonged survival, establishing a promising translational paradigm for overcoming TMZ resistance and boosting effective immunotherapy in GBM.
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