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Bai, Shuang; Lu, Zhixiang; Jiang, Yonghe; Shi, Xiaoxiao; Xu, Dazhuang; Shi, Yesi; Lin, Gan; Liu, Chao; Zhang, Yang; Liu, Gang
ACS nano, 01/2022, Volume: 16, Issue: 1Journal Article
Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.
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