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Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy

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Abstract

The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells (Treg), M2 macrophages (M2), and prostaglandin E2 (PGE2). The pivotal roles of PGE2 have been recognized by directly inactivating CD8+ T cells and indirectly inducing Treg and M2. Therefore, PGE2 abolishment through inactivating cyclooxygenase-2 (COX-2) could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy, which has gone into clinical trials. However, exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed. The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly. Thus, the programmed release nanoparticles (termed as Cele-BMS-NPs) are rationally designed, which are composed of pH-sensitive human serum albumin derivative, BMS-202 compound as PD-1/PD-L1 inhibitor, glutathione (GSH)-activatable prodrug of celecoxib (COX-2 inhibitor). The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment, and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells. After systemic administration, the intratumoral infiltration of CD8+ T cells is significantly enhanced and meanwhile immunosuppressive M2, Treg, and PGE2 are reduced, thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.

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Acknowledgements

We acknowledge the financial support from The National Key R&D Program of China (No. 2018YFA0903500), The Postdoctoral Science Fund of China (No. 2017M622429), The National Natural Science Foundation of China (No. 51703073), and The 1000 Young Talent Program of China. We also thank the Analytical and Testing Centre of HUST, Analytical and Testing Centre of School of Chemistry and Chemical Engineering (HUST), and Research Core Facilities for Life Sciences (HUST) for instrument support.

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  1. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China

    Liandong Feng, Li Yang, Longjie Li, Junying Xiao, Chao Xu, Jun Zhou, Hongmei Liu & Yuzhou Wu

  2. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, 430074, China

    Liandong Feng

  3. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Nana Bie & Lu Gan

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  1. Liandong Feng
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  2. Li Yang
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Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy

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Feng, L., Yang, L., Li, L. et al. Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy. Nano Res. 15, 593–602 (2022). https://doi.org/10.1007/s12274-021-3525-6

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