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Research Article

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

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.

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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

small interfering RNA (siRNA) deliverycollaborative assemblynanomedicineinsulin resistancediabetes

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Nano Research
Volume 13 Issue 11,
November 2020
Pages 2958-2966
DOI: 10.1007/s12274-020-2954-y
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
Topics:
BiosynthesisInsulinMacrophagesMammalsOrganic acids ProteinsRNA

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Received: 08 March 2020
Revised: 23 June 2020
Accepted: 25 June 2020
Published: 13 August 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
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