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Liposome-coated CaO2 nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

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Abstract

The blocking of the immune checkpoint pathway with antibodies, especially targeting to programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway, was currently a widely used treatment strategy in clinical practice. However, the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1. Herein, we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO2 (CaO2@Lipo) nanoparticles to inhibit the de novo biosynthesis of PD-L1. CaO2@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α (HIF-1α) level, which then downregulated the expression of PD-L1. Our in vitro and in vivo results have confirmed CaO2@Lipo promoted the degradation of HIF-1α and then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape. Furthermore, to mimicking the clinical protocol of anti-PD-L1 antibodies + chemo-drugs, CaO2@Lipo was combined with doxorubicin (DOX) to investigate the tumor inhibition efficiency. We found CaO2@Lipo enhanced DOX-induced immunogenic cell death (ICD) effect, which then promoted the infiltration of T cells, strengthened the blocking effect, and thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 31971304, 32271420, and 21977024), the Beijing-Tianjin-Hebei Basic Research Cooperation Project (No. 19JCZDJC64100), Cross-disciplinary Project of Hebei University (No. DXK201916), One Hundred Talent Project of Hebei Province (No. E2018100002), Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province (No. B2021201038), and Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515120065). We are grateful to Medical Comprehensive Experimental Center of Hebei University for the animal experiment.

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  1. Ruijun Che and Dandan Han contributed equally to this work.

Authors and Affiliations

  1. College of Chemistry & Environmental Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding, 071002, China

    Ruijun Che, Dandan Han, Miao Fan, Hongyu Yan, Zhaoshuo Wang & Jinchao Zhang

  2. Affiliated Dongguan Hospital, Southern Medical University, Dongguan, 523059, China

    Fei Wang, Xiaohan Zhou, Xueyi Wang, Caiwen Ou & Zhenhua Li

  3. Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, 510515, China

    Fei Wang, Xiaohan Zhou, Xueyi Wang, Caiwen Ou & Zhenhua Li

  4. College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, 071002, China

    Huifang Liu & Tingshan Xiao

  5. Department of Chemistry, the University of Manchester, Manchester, M13 9PL, UK

    Kaihan Zhang

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  1. Ruijun Che
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Correspondence to Jinchao Zhang or Zhenhua Li.

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Che, R., Han, D., Wang, F. et al. Liposome-coated CaO2 nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis. Nano Res. 16, 7227–7236 (2023). https://doi.org/10.1007/s12274-022-5362-7

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