Inhalable metal–organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy
作者机构:Department of PharmaceuticsKey Laboratory of Chemical Biology of Ministry of EducationSchool of Pharmaceutical SciencesCheelloo College of MedicineShandong UniversityJinan 250012China Key University Laboratory of Pharmaceutics&Drug Delivery Systems of Shandong ProvinceSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China
出 版 物:《Acta Pharmaceutica Sinica B》 (药学学报(英文版))
年 卷 期:2024年第14卷第5期
页 面:2281-2297页
核心收录:
学科分类:1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金:This work was partially funded by the Key R&D Programs of Shandong Province China(Grant Nos.2018CXGC1411 and 2021CXGC010514).
主 题:Cuproptosis Immunogenic cell death PD-L1 checkpoint blockade Copper-based metal-organic framework Immunotherapy Tumor microenvironment Transmucosal deliveryLung metastasis
摘 要:Cuproptosis shows enormous application prospects in lung metastasis treatment.However,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis efficacy.Herein,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely OMP.After inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa penetration.Within tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)regulation.Meanwhile,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis.Moreover,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells infiltration.Notably,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy efficacy.Overall,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.