Article Title

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

Authors

Shiyang Shen, § Shiyang Shen and Li Zhang contributed equally to this work.
Li Zhang, § Shiyang Shen and Li Zhang contributed equally to this work.
Mengru Li, § Shiyang Shen and Li Zhang contributed equally to this work.
Zhizi Feng, § Shiyang Shen and Li Zhang contributed equally to this work.
Huixia Li, § Shiyang Shen and Li Zhang contributed equally to this work.
Xiao Xu, § Shiyang Shen and Li Zhang contributed equally to this work.
Shiqi Lin, § Shiyang Shen and Li Zhang contributed equally to this work.
Ping Li, § Shiyang Shen and Li Zhang contributed equally to this work.
Can Zhang, § Shiyang Shen and Li Zhang contributed equally to this work.
Xiaojun Xu, § Shiyang Shen and Li Zhang contributed equally to this work.
Ran Mo, § Shiyang Shen and Li Zhang contributed equally to this work.

Keywords

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

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.

Graphical Abstract

DOI

https://doi.org/10.1007/s12274-020-2954-y

Publisher

Tsinghua University Press

Recommended Citation

Shiyang Shen,Li Zhang,Mengru Li,Zhizi Feng,Huixia Li,Xiao Xu,Shiqi Lin,Ping Li,Can Zhang,Xiaojun Xu,Ran Mo, Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance. NanoRes.2020, 13(11): 2958–2966