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Nano Research 2020, 13(11): 2958-2966 https://doi.org/10.1007/s12274-020-2954-y
Research Article | Issue | Published: 13 August 2020

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Show Author's Information Shiyang Shen§,  Li Zhang§,  Mengru Li,  Zhizi Feng,  Huixia Li,  Xiao Xu,  Shiqi Lin,  Ping Li,  Can Zhang,  Xiaojun Xu( ),  Ran Mo( )
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China

§ Shiyang Shen and Li Zhang contributed equally to this work.

Keywords:
nanomedicine, diabetes, small interfering RNA (siRNA) delivery, collaborative assembly, insulin resistance
Topics:
BiosynthesisInsulinMacrophagesMammalsOrganic acids ProteinsRNA
Cite this article:
Shen S, Zhang L, Li M, et al. Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance. Nano Research, 2020, 13(11): 2958-2966. https://doi.org/10.1007/s12274-020-2954-y
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Abstract Full text Electronic supplementary material About this article

Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes. Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators, therefore causing or aggravating insulin resistance. Herein, we develop collaborative assemblies using a "one-pot" synthesis method for macrophage-specific delivery of small interfering RNAs (siRNAs) that target the inflammatory proteins. Ternary nanocomplex (NC) composed of the siRNA molecule, a synthetic thiol-bearing methacrylated hyaluronic acid (sm-HA) and protamine forms through an electrostatic-driven physical assembly, which is chemically crosslinked to acquire the collaboratively assembled nanocapsule (cNC) concurrently. The obtained cNC displays significantly higher stability than NC. Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation, active targeting, or controlled siRNA release. cNC-F decorated with folic acid, a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model. cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins (> 40% reduction) and ameliorating the insulin resistance symptoms of the obese mice.


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Electronic supplementary material
About this article

Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance

Show Author's information Shiyang Shen§, Li Zhang§, Mengru Li, Zhizi Feng, Huixia Li, Xiao Xu, Shiqi Lin, Ping Li, Can Zhang, Xiaojun Xu( ), Ran Mo( )
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China

§ Shiyang Shen and Li Zhang contributed equally to this work.

Abstract

Obesity plays a primary causative role in insulin resistance and hyperglycemia that contributes to type 2 diabetes. Excess lipid storage in the liver renders activation of the resident macrophages and chronic secretion of inflammatory mediators, therefore causing or aggravating insulin resistance. Herein, we develop collaborative assemblies using a "one-pot" synthesis method for macrophage-specific delivery of small interfering RNAs (siRNAs) that target the inflammatory proteins. Ternary nanocomplex (NC) composed of the siRNA molecule, a synthetic thiol-bearing methacrylated hyaluronic acid (sm-HA) and protamine forms through an electrostatic-driven physical assembly, which is chemically crosslinked to acquire the collaboratively assembled nanocapsule (cNC) concurrently. The obtained cNC displays significantly higher stability than NC. Functional moieties as flexible assembly units can be easily equipped on cNC for long circulation, active targeting, or controlled siRNA release. cNC-F decorated with folic acid, a macrophage-targeting ligand promotes the siRNA accumulation in the activated macrophages in the liver of the obese mouse model. cNC-F loaded with siRNA targeting inflammatory indicators efficiently control the macrophage inflammatory response by reducing the expression of the inflammatory proteins (> 40% reduction) and ameliorating the insulin resistance symptoms of the obese mice.

Keywords: nanomedicine, diabetes, small interfering RNA (siRNA) delivery, collaborative assembly, insulin resistance

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Publication history
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Acknowledgements

Publication history

Received: 08 March 2020
Revised: 23 June 2020
Accepted: 25 June 2020
Published: 13 August 2020
Issue date: November 2020

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81673381, 81971730, and 81773957), the National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (No. 2019ZX09201001-001-001), the Project of State Key Laboratory of Natural Medicines of China Pharmaceutical University (Nos. SKLNMZZCX201820 and SKLNMZZ202024), the "Double First-Class" Project of CPU (Nos. CPU2018GF05 and CPU2018GF04), and the 111 Project (No. B16046). This work was also supported by the National Ten Thousand Talents Program for Young Top-notch Talents, the Program for Jiangsu Province Innovative Research Talents, and Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (171028) to R. M. X. X. and R. M. conceived and supervised the project. S. S., L. Z., X. X., and R. M. designed the experiments, analyzed, and interpreted the data, and wrote the manuscript. S. S., M. L., Z. F., and S. L. prepared and characterized the gene delivery system. S. S. and L. Z. performed in vitro cell studies. S. S., L. Z., H. L., and X. X performed in vivo animal studies. L. Z. and H. L. performed the Western-blot, RT-PCR, and ELISA analyses. P. L. and C. Z. contributed to discussion and provided relevant advice.

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