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Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application

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Abstract

Biologics play an essential role in treating various indications from cancers to the metabolic diseases, while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane. Hence, there remains an unmet need to develop safe, potent approaches to augment intracellular protein delivery efficiency. Here, we described a facile multi-component reaction system for generating a small library of redox-responsive cationic polypeptoids with high bio-compatibility. The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency, thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly. After endo-lysosomal escape, the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol, owing to the intracellular glutathione (GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone. As a result, we screened a promising platform reagent for efficient cytosolic protein delivery application.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (51803243, 51820105004), the Guangdong Basic and Applied Basic Research Foundation (2020A1515011285), and the Guangdong Innovative and Entrepreneurial Research Team Program (2013S086).

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Authors and Affiliations

  1. School of Materials Science and Engineering, Key Laboratory of Polymeric Composite and Functional Materials of Ministry of Education, GD Research Center for Functional Biomaterials Engineering and Technology, Sun Yat-sen University, Guangzhou, 510275, China

    Zhicheng Le, Tong Xiao, Zhijia Liu, Xingliang Liu, Lixin Liu & Yongming Chen

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  1. Zhicheng Le
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  2. Tong Xiao
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  3. Zhijia Liu
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  4. Xingliang Liu
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  5. Hong Liu
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  6. Lixin Liu
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  7. Yongming Chen
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Correspondence to Zhijia Liu or Yongming Chen.

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Le, Z., Xiao, T., Liu, Z. et al. Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application. Sci. China Chem. 63, 1619–1625 (2020). https://doi.org/10.1007/s11426-020-9802-0

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  • DOI: https://doi.org/10.1007/s11426-020-9802-0

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