Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold ...Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold nanoparticles(Au DENPs) as a nonviral vector to deliver programmed death-ligand 1(PDL1) small interfering RNA(siPD-L1) for subsequent PD-L1 gene silencing-mediated tumor immunotherapy. In this work,G5 dendrimers with amine termini were partially decorated with methoxy polyethylene glycol(m PEG) on their periphery,entrapped Au NPs within their interiors, and were eventually labeled with fluorescamine. The generated functional Au DENPs possess desired dispersibility in water and colloidal stability, satisfactory cytocompatibility after complexation with siPD-L1, and efficient gene delivery performance. Strikingly, the functional Au DENPs enabled the delivery of siPDL1 to cancer cells to efficiently knock down the PD-L1 protein expression, thus boosting the ICB-based immunotherapy of a xenografted melanoma mouse tumor model with a tumor inhibition efficiency much higher than the PD-L1 antibody.The immune responses were also well demonstrated by downregulation of PD-L1 protein on the tumor cell surface and abundant distribution of CD8+and CD4+T cells in the infiltrating tumor tissue and spleen organ. The developed functional dendrimer-based nanoplatform may be promising to boost ICB-based immunotherapy of other tumor types.展开更多
基金supported by the National Key R&D Program of China (2017YFE0196200)the National Natural Science Foundation of China (81761148028 and 21773026)+3 种基金the Science and Technology Commission of Shanghai Municipality (19XD1400100,205207130300,20DZ2254900 and 19410740200)support by FCT-Funda??o para a Ciência e a Tecnologia through the CQM Base Fund—UIDB/00674/2020Programmatic Fund—UIDP/00674/2020ARDITI-Agência Regional para o Desenvolvimento da Investiga??o Tecnologia e Inova??o,through the project M1420-01-0145-FEDER-000005—Centro de Química da Madeira—CQM+ (Madeira 14-20 Program)。
文摘Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold nanoparticles(Au DENPs) as a nonviral vector to deliver programmed death-ligand 1(PDL1) small interfering RNA(siPD-L1) for subsequent PD-L1 gene silencing-mediated tumor immunotherapy. In this work,G5 dendrimers with amine termini were partially decorated with methoxy polyethylene glycol(m PEG) on their periphery,entrapped Au NPs within their interiors, and were eventually labeled with fluorescamine. The generated functional Au DENPs possess desired dispersibility in water and colloidal stability, satisfactory cytocompatibility after complexation with siPD-L1, and efficient gene delivery performance. Strikingly, the functional Au DENPs enabled the delivery of siPDL1 to cancer cells to efficiently knock down the PD-L1 protein expression, thus boosting the ICB-based immunotherapy of a xenografted melanoma mouse tumor model with a tumor inhibition efficiency much higher than the PD-L1 antibody.The immune responses were also well demonstrated by downregulation of PD-L1 protein on the tumor cell surface and abundant distribution of CD8+and CD4+T cells in the infiltrating tumor tissue and spleen organ. The developed functional dendrimer-based nanoplatform may be promising to boost ICB-based immunotherapy of other tumor types.
