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Regulation of the cellular uptake of nanoparticles by the orientation of helical polypeptides

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Abstract

Controlling the cellular interaction and internalization of polymer-modified nanoparticles (NPs) is of central importance to the development of promising nanomedicines. Here, we describe the use of synthetic polypeptides for NP surface coating and regulation of their cellular uptake behaviors by simply switching the conformation and anchoring orientation. Our results show that gold NPs (AuNPs) coated with a helical poly(γ-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)esteryl L-glutamate) (L-P(EG3Glu)50) from the C-terminus ((L-C)-AuNPs) exhibit greater zeta potential and more cellular uptake (2.0–5.5 fold higher) than those coated with the same polypeptide but anchored from the N-terminus ((L-N)-AuNPs), or from both the C- and N-terminus at a 1/1 molar ratio ((L-C/L-N)-AuNPs). A similar orientation-regulated cellular internalization pattern is observed in D-P(EG3Glu)50 but not the unstructured DL-P(EG3Glu)50-modified AuNPs, suggesting an important and universal role of the helix-derived macrodipole in cellular uptake. Moreover, this orientation-governed internalization is successfully reproduced in P(EG3Glu)50-coated gold nanorods (AuNRs), and applied to the design of doxorubicin-loaded polypeptide micelles. Simulation study offers time-resolved insights regarding the NP–membrane interactions and membrane remodeling. Thus, our study provides a delicate way of regulating the surface chemistry of NPs and the subsequent NP–cell interactions. Moreover, the results highlight the uniqueness of polypeptides in NP surface engineering, and urge a more careful consideration on the polymer orientation effect.

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Acknowledgments

Financial supports from the National Key Research and Development Program of China (No. 2016YFA0201400) and the National Natural Science Foundation of China (No. 21722401) are gratefully acknowledged.

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  1. Chong Zhang, Jianhua Lu, and Falin Tian contributed equally to this work.

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China

    Chong Zhang, Jianhua Lu, Lindong Li, Yingqin Hou, Yaoyi Wang, Lingdong Sun & Hua Lu

  2. Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, Peking University, Beijing, 100871, China

    Chong Zhang, Jianhua Lu, Yingqin Hou, Yaoyi Wang & Hua Lu

  3. CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China

    Falin Tian & Xinghua Shi

  4. State Key Laboratory of Rare Earth Materials Chemistry and Applications, PKU-HKU Joint Laboratory in Rare Earth Materials and Bioinorganic Chemistry, Peking University, Beijing, 100871, China

    Lindong Li & Lingdong Sun

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  1. Chong Zhang
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Correspondence to Lingdong Sun, Xinghua Shi or Hua Lu.

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Zhang, C., Lu, J., Tian, F. et al. Regulation of the cellular uptake of nanoparticles by the orientation of helical polypeptides. Nano Res. 12, 889–896 (2019). https://doi.org/10.1007/s12274-019-2319-6

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