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-L1mediated 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.

The rational design of tumor microenvironment (TME)‐activated nanomedicine is driving a new direction in tumor immunology. Furthermore, the novel therapeutic mode of ultrasound‐triggered sonodynamic therapy (SDT) has been proven to specifically activate the immune response. Herein, a well‐defined covalent organic framework (COF) with sonosensitive properties is synthesized through experimental and theoretical verification, followed by the efficient loading of the toll‐like receptor agonist (Poly(I:C)) and in situ growth of paramagnetic transitional metallic oxide of manganese bioxide (MnO2). The MnO2‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn2+, simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H2O2) and produce oxygen, facilitating SDT‐induced reactive oxygen species production, and inducing immunogenic cell death, thereby boosting immune engine and triggering abundant neoantigen exposure. With the powerful assistance of immunological agents Mn2+ and Poly(I:C), the triggered immune engine is amplified by refueling the engine (stepping on the accelerator) to reduce the immunosuppressive state. Overall, this study improves the synthesis of multifunctional COF and expands its application. The developed nano‐sonosensitizer system provides a paradigm to enhance SDT‐based high‐performance multifunctional sonosensitizers, and this SDT‐mediated strong tumor‐suppressive efficiency and activated immune effect represent a promising combinatorial therapeutic strategy for cancer therapy.

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endocytose, process and present tumorassociated antigens (TAAs) to T cells and other immune cells, thus directly initiating a potent and tumor-specific immune response. [2] However, some mechanisms in the tumor microenvironment enable tumor cells to evade immune surveillance through limiting DCs antigens processing and presentation to CD8 + T cells. [3] Therefore, promoting tumor antigens uptake and cross-presentation by DCs would profoundly activate T cell-mediated immune response to eradicate tumors. DEC-205, an endocytic receptor of C-type multi-lectin, is highly expressed on the surface of DCs and responsible for the antigens processing and presentation. Anti-DEC205, a specific antibody, which can interact with DEC205 resulting in antigens cross-presentation and T-cells priming. [4] Moreover, enhancing immune response with DCs also largely depends on the derivation, formation and variety of TAAs to inspire antitumor immunity. [5] Besides, recent studies have reported that targeting DEC-205 with anti-DEC205-specific TAAs (e.g., melanoma tumor antigen gp100) fusion proteins to initiate a potent tumor-specific immune response. [3c,6] However, the selective tumor antigen in the fusion proteins may not effectively activate antitumor immune response driven by antigens loss or the selection of one or a few validated TAAs. [6a,7] Given that, tumor cell membrane vesicles can completely inherit the properties of sourced cancer cells including the membrane antigens without antigens loss, and they have been widely studied as tumor vaccines or tools of synergistic therapies. [8] Furthermore, combining the tumor cell membrane vesicles with anti-DEC205 would significantly trigger DCs activation, maturation and tumor antigens cross-presentation, thus enhancing cascade amplified T-cell immune response and improving immunotherapeutic efficacy. [9] However, mono-immunotherapy can hardly achieve desired therapeutic efficacy in cancer therapy, and often need to synergize with other therapies such as chemotherapy, [10] photothermal therapy [11] and radiotherapy. [12] Compared with conventional synergetic strategies, cells membrane coated nano particles can simultaneously retain the immune functions of the sourced cells and the multifunctionality of the Despite recent advancements of sonodynamic therapy (SDT) in cancer immunotherapy, challenges have yet to be surmounted to further boost its immunotherapeutic efficacy due to the low-level tumor antigens presentation of dendritic cells (DCs). Cell membrane camouflaged-nanoparticles can integrate the neoantigens of the cancer cell membrane with the multifunctionalities of synthetic nanocores. Herein, sono-responsive nanoparticles coated with DC-targeted antibody chimeric cancer cell membrane are investigated for multimodal therapy. The nanometal organic frameworks (MOFs) that respond to ultrasound are loaded successfully inside the vesicles displaying an anti-DEC205 antibody. The anti-DEC205 chimeric vesicles can directly target and activate DCs, promote tumor antigens cross-pr...

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