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A programmable polymer library that enables the construction of stimuli-responsive nanocarriers containing logic gates

Nature Chemistry volume 12, pages 381–390 (2020)Cite this article

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Abstract

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this ‘plug and play’ platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.

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Fig. 1: Rational design of SNCs using a polymer library for logic computation and sequential drug release.
Fig. 2: Construction of the stimuli-responsive polymer library.
Fig. 3: Biocomputation using logic-gated nanocarriers.
Fig. 4: pH-activated targeting, sequential release and logic computation in vitro.
Fig. 5: Enhanced antitumour efficacy in vivo using combinatorial treatment.

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Data availability

All the datasets generated and/or analysed during this study and supporting the findings described are available within the article and its Supplementary Information or from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (21605118, 21974105, 11522219, 11972280, 11532009, 21427807, 21834004, 21827811 and 61527806), the China Postdoctoral Science Foundation (2015M580829 and 2017T100735), the Postdoctoral Science Foundation of Shaanxi Province (2016BSHTBSHTDZZ01), the Natural Science Foundation of Shaanxi Province (2018JQ2001), the Open Funds of SKLACLS from Nanjing University (1508) and the Fundamental Research Funds for the Central Universities (xjj2015081). Z.P. also acknowledges financial support from the program of China Scholarships Council. J.Z. thanks the support from Excellent Research Program of Nanjing University (ZYJH004). Correspondence and requests for materials should be addressed to W.T., F.X. or J.-J.Z.

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Author notes

  1. These authors contributed equally: Penghui Zhang, Di Gao, Keli An.

Authors and Affiliations

  1. The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, and Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an, China

    Penghui Zhang, Keli An, Xiaoman Duan, Jie Liu, Tielin Yang & Feng Xu

  2. Center for Research at the Bio/Nano Interface, Department of Chemistry and Department of Physiology and Functional Genomics, UF Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Penghui Zhang, Xiaoshu Pan, Xigao Chen, Yifan Lyv & Cheng Cui

  3. State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Di Gao, Qi Shen, Chen Wang, Yuchao Zhang, Tingxizi Liang & Jun-Jie Zhu

  4. Institute of Molecular Medicine (IMM), Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Yifan Lyv, Cheng Cui & Weihong Tan

  5. Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China

    Yifan Lyv & Weihong Tan

  6. Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha, China

    Cheng Cui, Xiaoxiao Hu & Weihong Tan

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Contributions

P.Z., J.-J.Z., F.X. and W.T. conceived the project, analysed the data and discussed the writing of the paper. P.Z., D.G., K.A., Q.S., Y.Z., X.C., X.D. and J.L. designed the monomers and performed the organic synthesis experiments. P.Z., K.A., C.W., X.P., T.L., C.C., Y.L. and X.H. performed the in vitro and in vivo experiments and analysed the data. T.Y. analysed the gene expression levels from the CCLE and TCGA databases. P.Z., W.T. and F.X. wrote the manuscript. P.Z., D.G. and K.A. contributed equally to this work.

Corresponding authors

Correspondence to Jun-Jie Zhu, Feng Xu or Weihong Tan.

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Methods, additional discussion, Supplementary Figs. 1–20, Tables 1–4, profiles of gene expression, and references.

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Zhang, P., Gao, D., An, K. et al. A programmable polymer library that enables the construction of stimuli-responsive nanocarriers containing logic gates. Nat. Chem. 12, 381–390 (2020). https://doi.org/10.1038/s41557-020-0426-3

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